Medical Director Austin Hepatitis Center 1 Hepatitis C amp PCPs 2 LACK OF AWARENESS LACK OF APPROPRIATE ACTION Expand Quantitative Landscape Study Oct 2013 Gilead Sciences 3550 of PCP believe HCV can be cured ID: 748677
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Slide1
Hepatitis C
Imtiaz Alam, M.D.Medical Director, Austin Hepatitis Center
1Slide2
Hepatitis C & PCP’s
2
LACK OF AWARENESS
LACK OF APPROPRIATE ACTION
Expand Quantitative Landscape Study – Oct 2013 [Gilead Sciences]
35-50% of PCP believe HCV can be cured
<10% Aware of DAA’s and new treatment regimens
20% Plan to screen all baby boomers
50% PCP consider LFT’s as their “Initial” screen
<25% pf PCPs order HCV RNA test
Only 20% of PCP “Would Definitely” refer an asymptomatic patientSlide3
3
The Critical Questions?
WHY
WHO
HOW
WHAT
Is There An Urgent Need For HCV Diagnosis?
Is Most at Risk For HCV and What Is the Guidance on Testing?
How Can You Test Patients For HCV At The Point of Care?
Can You Do To Ensure Your Patients Are Not Only Tested But Linked to Care?Slide4
4
Action Plan
Aware
Engage
Act
Drive Awareness of HCV and Treatment Actions
Cultivate Interest and Intent to Learn
Prompt consistent and Quality
Screening, Diagnosis and Referral Slide5
5
An RNA virus that used to be known as non-A,
non-B hepatitis until it was discovered in 1988
1
No vaccine available
First therapy approved in 1986
2
Before 2011, HCV treatment could last as long as
a year, with cure rates sometimes being at 40%-50%
3
Since that time, scientific advances have made
HCV treatment shorter and more effective than
it was previously
HCV History
1. CDC.
MMWR
Morb
Mortal
Wkly
Rep.
1998;47(RR-19):1-39.
2. FDA.
http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm151494.htm
.
3.
Ghany
MG et al.
Hepatology
. 2011;54(4):1433-1444.Slide6
6
Epidemiology of HCV Infection: United States
Approximately 3.2 million persons in the United States have chronic hepatitis C virus (HCV) infection
1,a
Seroprevalence
is higher among
2
Individuals born between 1945-1965 (3.5%)
Black non-Hispanics (2.2%)
Males (1.9%)
6
a
This
figure may be an underestimate because the sampling frame of National Health and Nutrition Examination Survey (NHANES) did not include certain high-risk populations.
4
1. Armstrong GL, et al.
Ann Intern Med.
2006;144:705-714; 2.
Ditah
I, et al.
J
Hepatol
.
2013 Nov 27 [
Epub
ahead of print];
3.
Nainan
OV, et al.
Gastroenterology.
2006;131:478-84
; 4.
Chak
E, et al.
Liver Int.
2011;31:1090-1101.
Distribution of HCV Genotypes (GTs) in the US
3Slide7
7
HCV and HIV-1 Co-infection
Of people with HIV-1 in the US, about 25% are co-infected with HCV
1
About 85% of people with HIV who inject drugs also have HCV infection
2
HIV infection in a person who is also infected with HCV results in
2
Higher levels of HCV in the blood
More rapid progression to HCV-related liver disease
Increased risk for cirrhosis and HCC
7
1. Thomas DL.
Ann Rev Med.
2008; 59:473-485; 2.
Sulkowski
MS, Thomas DL.
Ann Intern Med.
2013;138:197-207.
All HIV-infected
1
HIV-infected
Injection-drug users
2
HCC = hepatocellular carcinoma; HIV = human immunodeficiency virus.Slide8
8
8
Population Studies Show a Significant Gap in Hepatitis c Care in the United States
Yehia BR,
et al.
PLoS One
. 2014;9:e101554
.
Zein
NN, et al.
Ann Intern Med
. 1996;125:634-639
.
Chronic HCV
infection
Diagnosed and aware
Access to outpatient care
Prescribed HCV treatment
Achieved sustained virologic response (SVR)
50%
43%
16%
9%
73%
GT 1a
2
27%
GT 1b
2
3.5 Million
79%
Genotype (
GT) 1
2
US Cascade of Care, 2003-2013
1Slide9
Natural History
9
Acute Infection*
Chronic Infection
75%-85%
Clearance of
HCV RNA
15%-25%
Extrahepatic
Manifestations
Cirrhosis
10%-20% over 20 years
HCC
1%-4% per year
Decompensated
Cirrhosis
5-yr survival rate 50%
Adapted from Chen SL, Morgan TR.
Int
J Med Sci
. 2006;3:47-52
.
*20%-30% of individuals are symptomatic.
HCC=hepatocellular carcinoma.Slide10
10
Host Factors Associated with More Rapid Disease Progression
1. Malnick S, et al.
Drugs Aging.
2014;31:339-347; 2. Maasoumy B, Wedemeyer H.
Best Pract Res Clin Gastroenterol.
2012;26:401-412; 3
. Nishida N, et al.
Dig Dis.
2012;30:547-553; 4. Noureddin M, et al.
Hepatology.
2013;58:1548-1557;
5
. Missiha SB, et al.
Gastroenterology.
2008;134:1699-1714; 6. Yoon YH, et al.
Alcohol Clin Exp Res.
2011;35:240-249; 7
. Younossi ZM, Stepanova M. Clin Gastroenterol Hepatol. 2010;8:718-723.
Nonmodifiable Host Factors
Older
age at infection
Associated with accelerated cirrhosis development
1
Increasing age (longer duration of infection)
Associated with accelerated fibrosis progression
1
Male gender
Associated with accelerated fibrosis progression and more frequent HCC development
2,3
IL28B
CC allele
More likely to develop adverse
clinical outcomes
a
but not associated with fibrosis progression
4
Transfusion-associated HCVAssociated with accelerated progression to cirrhosis (versus community- or childhood-acquired HCV)5
Hispanic ethnicityHigher mortality rates from HCV-related cirrhosis6 Hispanic ethnicity is an independent risk factor for HCC-related mortality7Caucasian
Increased histologic activity and incidence of cirrhosis (as compared to blacks)
2
a
Clinical outcomes were defined as one of the following: death, development of ascites, spontaneous bacterial peritonitis, variceal hemorrhage, hepatic encephalopathy, HCC, and increase in Child-Pugh-Turcotte score by ≥2 points on 2 consecutive clinic visits 12 weeks apart.
10Slide11
Host Factors Associated with More Rapid Disease Progression (cont.)
HBV = hepatitis
B virus.
a
Moderate and high consumption were defined as 1-19 g/day and ≥30 g/day, respectively.
2
b
Lifetime consumption of ≥20 pack-years.
c
Liver biopsy staging/fibrosis score ≥4.
3
1. Lim JK, et al.
Clin Infect Dis.
2014;58:1449-1458; 2. Younossi ZM, et al
. Aliment Pharmacol Ther.
2013;37:703-709; 3. Tsochatzis E, et al.
Scand J Gastroenterol.
2009;44:752-759; 4. Kang W, et al.
Expert Rev Gastroenterol Hepatol.
2014;8:247-266; 5. Oh JK, et al.
BMC Cancer.
2012;12:452; 6. Lambrecht RW, et al.
Gastroenterology.
2011;140:1490-1500; 7. Goossens N, Negro F.
Clin Liver Dis.
2014;18:147-156; 8. Hung CH, et al.
World J Gastroenterol.
2010;16:2265-2271; 9. El Ray A, et al.
Eur J Gastroenterol Hepatol.
2013;25:421-427; 10.Ghany MG, et al.
Gastroenterology. 2010;138:136; 11. Kurosaki M, et al. Hepatol Res. 2010;40:870-877.
Behavioral and Clinical/Laboratory Host Factors
Moderate to high alcohol consumption
a
Associated with significant risk of advanced hepatic fibrosis and mortality (all-cause and liver-related)
1,2
Heavy smoking
b
Factor for severe fibrosis
c
in CHC
3
HIV-1 co-infection
Associated with higher viral load, rapid progression to cirrhosis, liver failure, and HCC
4
HBV co-infection
Associated with increased risk of HCC
5
Iron overload
Correlated with decompensated cirrhosis, HCC, or death
6
Combined obesity and diabetes mellitus
Associated with 100-fold increase in risk of HCC
development
7
Insulin resistance
Independent predictor of HCC development
8
and associated with increasing fibrosis
9
Hepatic steatosis
Associated with ≥2-point increase in Ishak fibrosis score
10
and HCC development
11
Platelet counts, AST/ALT ratio, bilirubin, and albumin
Independent predictors of fibrosis progression or clinical decompensation
10
11Slide12
12
Cumulative Incidence of Fibrosis Progression
Year
Year
Progression to fibrosis stage 1-2
1
Progression to fibrosis stage 3-4
1
1. Bochud PY, et al.
J Hepatol.
2009;51:655-666; 2. Kanwal F, et al.
Hepatology.
2014;60:98-105.
HCV GT 3 Was Associated with Accelerated Fibrosis Progression and Increased Risk of HCC
GT 3 was associated with accelerated fibrosis progression
1
Patients from the Swiss Hepatitis C Cohort Study enrolled before December 2008 (N=1189)
GT 3 was associated with an increased risk of developing HCC
2
Retrospective study of patients in the VA HCV Clinical Case Registry, 2000-2009
Proportion Free of HCC
Incident HCC
2
Year
Adjusted HR
a
=1.8 (1.61, 2.03)
a
Adjusted for
prespecified
demographic, clinical, and treatment
factors.
2
HR = hazard ratio;
VA = Veterans Administration
.
1.00
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0.00
0
5
10
15
20
25
30
35
40
GT 1 or 4
(n=492
, ref)
GT 2
(n=65
,
P
=.003)
GT 3
(n=244
,
P
<.001)
0
5
10
15
20
25
30
35
40
GT 1 or 4
(n=630
, ref)
GT 2
(n=92
,
P
=.04)
GT 3
(n=342
,
P
<.001)
1.00
0.98
0.96
0.94
0.92
0.90
0.88
0.86
0.84
0.82
0.80
0
1
2
3
4
5
6
7
11
GT 1 (n=88,348)
GT 2 (n=13,077)
GT 3 (n=8,337)
GT 4 (n=1,082)
8
9
10
N=110,484Slide13
13
HCV Is Leading Cause of Liver Transplants in the US
Available at: http://srtr.transplant.hrsa.gov/annual_reports/2011/pdf/03_%20liver_12.pdf.
Primary cause of disease among adult liver transplant recipients, 2011
All others
22.3%
Acute hepatic necrosis
Alcoholic
liver disease
17.6%
HCV
23.5%
Cholestatic disease
Metabolic liver disease
Malignancy
20.9%
2.5%
4.0%
All others
26.4%
Acute hepatic necrosis
Alcoholic liver disease
23.2%
HCV
30.1%
Cholestatic disease
HBV
Malignancy
2.6%
2.8%
Primary cause of disease among adults on the liver transplant wait list, 2011
6.0%
9.0%
9.1%Slide14
14
Annual Prevalence Rates Between 1996 and 2006 Among HCV-Infected Veterans
Progressive Increase in Incidence of
HCV-Related Cirrhosis and HCC in US
El-
Serag
HB.
Gastroenterology
2012;142:1264–1273.Slide15
15
Presentation of Patients Infected With HCV
Patients often asymptomatic in early stages of infection
1
1. http://www.cdc.gov/knowmorehepatitis/Media/PDFs/FactSheet-ChronicHepC-GenInfo.pdf; 2.Ali A, Zein NN.
Cleve Clin J
Med.
2005;72:1005-1008.
Fever
Fatigue
Loss of appetite
Nausea
Vomiting
Abdominal pain
Dark urine
Grey-colored stools
Jaundice
Joint pain
Symptoms may include
1
Arthralgias
Paresthesias
Myalgias
Pruritus
Sicca
syndrome
First symptoms may be those of
extrahepatic
manifestations
2Slide16
16
Extrahepatic
Manifestations of HCV
Mixed cryoglobulinemia
Sjögren (sicca) syndrome
Lymphoproliferative disorders
Porphyria cutanea tarda
Neuropathy
Membranoproliferative glomerulonephritis
Cryoglobulinemic vasculitis
Corneal ulcers
(Mooren ulcers)
Thyroid disease
Lichen planus
Pulmonary fibrosis
Type 2 diabetes
Systemic vasculitis (polyarteritis nodosa, microscopic polyangiitis)
Arthralgias, myalgias, inflammatory polyarthritis
Autoimmune thrombocytopenia
Adapted from Ali A, Zein NN.
Cleve Clin J
Med.
2005;72:1005-1008.
Strongly associated
Possibly associatedSlide17
17
Mortality Rates in the US, 1999-2007
*Mortality rates = HBV, HCV, HIV listed as cause of death
Because decedent can have multiple causes of death, a record listing more than 1 type of infection was counted for each type of infection
Ly KN, et al. Ann Intern Med. 2012;156:271-278.
7
6
5
4
3
2
1
0
1999
2001
2002
2003
2004
2005
2006
2007
2000
Rate per 100,000 PY*
Yr
Hepatitis B
Hepatitis C
HIVSlide18
Property Of BioCentra, LLC
18
HCV Viral Replication Associated With Higher All-Cause Mortality
Lee MH, et al. J Infect Dis. 2012;206:469-477.
All Causes
Cumulative Mortality (%)
30.1%
12.8%
12.4%
P
< .001 for comparison among 3 groups
P
< .001 for HCV RNA detectable vs undetectable
Anti-HCV seropositives, HCV RNA detectable
Anti-HCV seropositives, HCV RNA undetectable
Anti-HCV seronegatives
Follow-up (Yrs)
0
2
4
6
8
10
12
14
16
18
20
35
30
25
20
15
10
5
0
18Slide19
19
Liver Transplant Projection From 2013 to 2043
Potential Transplant Need: Treatment of all candidates and SVR of 90% will still require ≈22,000 transplants/year in 2033
Number of Persons
20,000
0
5
10
15
20
25
30
40,000
60,000
80,000
100,000
120,000
140,000
160,000
180,000
0
Year in Model
150,617
162,559
162,747
24,258
21,994
49,013
91,310
126,296
18,193
25,573
27,175
26,207
No treatment
25% treated
50% treated
75% treated
All treated
Desai
et al. AASLD 2013. Abstract
1427Slide20
Healthcare Costs
20
Razavi
H, et al.
Hepatology
. 2013.
Epub
ahead of print.
Prevalence
(95% CI)
Health Care Cost
(95% CI)
While the prevalence of HCV infection is declining from its peak, the incidence of advanced liver disease and associated health care costs continue to rise
Modeling does not take into account any impact of birth cohort screening
A system dynamic modeling framework was used to quantify the HCV-infected population, the disease progression, and the associated cost from 1950-2030.
CI=confidence interval.
Prevalence (Million)
Health Care Cost (Billion)Slide21
21
Average Annual All-Cause Healthcare Costs
Patient Population
Mean Annual All-Cause Healthcare
Cost per Person, $
HCV uninfected
[1]
9979
HCV
positive, noncirrhotic
[2
]
17,277
HCV positive, compensated cirrhosis
[2]
22,752
HCV positive, ESLD
[2]
59,995
1.
McAdam-Marx C, et al. J Manag Care Pharm. 2011;17:531-546.
2. Gordon SC, et al. Hepatology. 2012;56:1651-1660.Slide22
22
HCV-Related Health Care Costs
by Liver Severity (USD 2010)
Gordon SC, et al.
Hepatology
. 2012;56:1651-1660.
Numbers in parentheses are
+
SD. *
P
<0.001 versus non-cirrhotic liver disease.
HCV-Related Costs
(per-patient-per-month)
Total
Total Health
Care Costs
Inpatient
Ambulatory
Pharmacy
Costs
Medical Costs
650
(2714)
1060*
(2941)
3505*
(10,996)
467
(2648)
663*
(2815)
3328*
(10,996)
313
(2587)
334
(2674)
2608*
(10,359)
130
(444)
304*
(587)
579*
(1721)
183
(612)
404*
(847)
177*
(591)
Non-cirrhotic liver disease (n=41,858)
Compensated cirrhosis (n=3718)
End-stage liver disease (n=8220)Slide23
23
Patients Should be Screened for HCV According to Birth Cohort and Risk Factors
1,2
Smith BD, et al.
MMWR Recomm Rep
. 2012;61:1-32.
Moyer VA; US Preventive Services Task Force.
Ann Intern Med
. 2013;159:349-357.
Persons
Born Between
1945
and
1965
1,2
The 1945-1965 birth cohort was selected on the basis of HCV prevalence and disease burden
One-time screening for HCV infection in
the birth cohort may identify infected patients at earlier stages of disease
Birth Cohort Screening
Risk
Factor–Based
Screening
Past or current injection drug use
Receiving a blood transfusion before 1992
Long-term hemodialysis
Being born to an HCV-infected mother
Incarceration
Intranasal drug use
Getting an unregulated tattoo
Other percutaneous exposures
Important Risk
Factors
1,2
Patient Screening for HCVSlide24
24
www.prevent.org/National-Commission-on-Prevention-Priorities/Rankings-of-Preventive-Services-for-the-US-Population.aspx.
Rein DB, et al.
Ann Intern Med
. 2012;156:263-270.
2-Drug
Treatment
Cost Per QALY Saved (Dollars)
Cost-Effectiveness of HCV Testing vs Other Routine Preventive Services
*Birth cohort testing, 1945-1965.
2-drug treatment=PegIFN+RBV; 3-drug treatment=PegIFN+RBV+PI.
QALY=quality-adjusted life-year.
With Treatment
With Treatment
3-Drug
TreatmentSlide25
25
Laboratory Diagnosis of Chronic HCV Infection
RNA testing identifies active disease in HCV- seropositive patients
HCV antibodies appear by
6–8 weeks following infection
1
Can be detected by EIA
2
Serum ALT is not a reliable indicator of liver damage
1
FDA-approved rapid point-of-care testing is available
3
OraQuick® HCV Test
Image adapted from MicrobiologyBytes:Virology:HCV
1
1. www.microbiologybytes.com/virology/HCV.html; 2. Alter MJ, et al.
MMWR
Recomm
Rep
. 2003;52(RR-3):1-13, 15;
3.
Shivkumar
S, et al.
Ann Intern Med
. 2012;157:558-566.
ALT=alanine aminotransferase; EIA=enzyme immunoassay; RNA=ribonucleic acid; ULN=upper limit of normal.
Time After Exposure
Months
Years
0
1
2
3
4
5
6
1
2
3
4
Titer
Anti-HCV
ALT
Symptoms +/–
HCV RNA
ULN
ALT (U/L) Slide26
26
HCV Diagnostic Algorithm Based on
Serologic Testing
Ghany MG, et al.
Hepatology
. 2009;49:1335-1374
.
*If patient lacks pre-existing antibodies to HAV or HBV.
HAV=hepatitis A virus, HBV=hepatitis B virus.
Anti-HCV Antibody
HCV RNA
No Further Testing
No Active Disease
Positive
Positive
Negative
Negative
HCV Genotype
Consider Liver Biopsy
Vaccinate for HAV / HBV*Slide27
27Slide28
28
Scoring Systems for Histologic Stage
1. Bedossa P, Poynard T.
Hepatology
. 1996;24:289-293; 2. Ishak K, et al.
J Hepatol
. 1995;22:696-699.
Figure adapted from Standish RA, et al.
Gut
. 2006;55:569-578.
Appearance
Ishak
Description
Ishak
Score
1
METAVIR
Score
2
No fibrosis
0
F0
Fibrous expansion of some portal areas ± short fibrous septa
1
F1
Fibrous expansion of most portal areas ± short fibrous septa
2
F2
Fibrous expansion of most portal areas with occasional portal to portal (P–P) bridging
3
Fibrous expansion of most portal areas with marked bridging (P–P and portal to central [P–C])
4
F3
Marked bridging (P–P and/or P–C) with occasional nodules (incomplete cirrhosis)
5
Cirrhosis
6
F4Slide29
29
Invasive and Noninvasive Fibrosis Tests
Liver Biopsy
Serum Markers
Transient
Elastography
MRE
Methodology
Direct observation
Measures direct and
indirect serum markers* of fibrosis
Liver stiffness by detection of ultrasound-propagated shear waves
Liver stiffness by MRI of
vibration-propagated shear waves
Accuracy for detecting cirrhosis
High
Moderate (APRI) to high (
FibroSURE
TM
, ELF)
High
High
Accuracy for detecting intermediate fibrosis
High
Low (APRI) to moderate (
FibroSURE
TM
, ELF)
Moderate to high
High
Risk of complications
Risk of pain/bleeding
Minimal
Minimal
Minimal
Contraindications
Coagulopathy
Minimal
Obesity;
narrow rib spaces
Claustrophobia; other MRI contraindications
Limitations
Sampling error
Observer
variation
False-positives
with
hemolysis, inflammation, Gilbert’s syndrome
False-positives with inflammation, congestion
False-positives with inflammation, congestion
Longitudinal monitoring
Unsuitable
Indices may change with disease progression / therapy
Liver stiffness changes with disease progression / therapy
Liver stiffness changes with disease progression / therapy
Cost
Highest per-test cost
Low per-test cost
High initial equipment cost
Very high initial equipment cost
Nguyen D,
Talwalkar
JA.
Hepatology
. 2011;53:2107-2110.Slide30
FibroScan
30Slide31
31
Indirect Serum Tests for Fibrosis
Test
Test
C
omponents
Sensitivity (%)*
Specificity
(%)*
PPV (%)*
NPV (%)*
Cirrhosis Discrimination
Fibrosis Discrimination
AST/ALT
ratio
1
AST,
ALT
53
100
100
81
+
–
APRI
2
AST/platelet count
77
72
70
79
+
+/– (moderate)
FIBROSpect
II®
3,4
HA, TIMP-1,
a
2-
macroglobulin
72
74
61
82
+
+
FibroSURE
TM
5,6
FibroTest
a
2-macroglobulin,
haptoglobin
, Apo A1, GGT, total bilirubin, ALT
84
95
76
91
+
+
HepaScore®
7
Age, gender, bilirubin, GGT, HA,
g
2-
macroglobulin
77
70
71
77
+
+
ELF
8
HA
, N-terminal
propeptide
of type III collagen, TIMP-1
86
62
80
70
+
+
1. Sheth SG, et al.
Am J Gastroenterol
. 1998;93:44-48; 2. Lin ZH et al.
Hepatology
. 2011;53:726-736; 3. Zaman A, et al.
Am J Med
. 2007;120:280.e9-e14;
4. www.prometheuslabs.com/Resources/Fibrospect/Fibrospect_II_Product_Detail.pdf; 5. Poynard T, et al.
Comp Hepatol
. 2004;3:8;
6. www.labcorp.com/.EdosPortlet/TestMenuLibrary?libName=File+Library&compName=L1080;
7. Guéchot J, et al.
Clin Chim Acta
. 2010;411:86-91; 8. Guéchot J, et al.
Clin Chem Lab Med
. 2012 ;50:693-699.
ALT=alanine aminotransferase; Apo A1=apolipoprotein A1; GGT= gamma-glutamyl transpeptidase; HA=hyaluronic acid; NPV=negative predictive value; PPV=positive predictive value; TIMP-1=tissue inhibitor of metalloproteinase.*Sensitivity, specificity, PPV, and NPV values are for significant fibrosis, with the exception of AST/ALT ratio, where the values are for cirrhosis.Slide32
32
Counseling Recommendations for
HCV-Infected Individuals
Avoid sharing toothbrushes and dental or shaving equipment
Prevent blood contact with others
Stop using illicit drugs; those who continue to inject drugs should take precautions to avoid viral transmission
Risk of sexual transmission is low, but practice “safe sex”
Avoid alcohol consumption
Excess alcohol may lead to progressive liver disease, increased HCV RNA replication, and reduced response to treatment
Consider treatment for hepatitis C*
Vaccinate for hepatitis A and B
Get tested for HIV
Encourage family members to get screened
Additional Recommendations
To Prevent HCV Transmission
*If patient meets generally accepted indications for HCV treatment.
Adapted from Ghany MG, et al.
Hepatology
. 2009;49:1335-1374.Slide33
33
Images adapted from Soriano V, et al.
1
1. Soriano V, et al.
J Antimicrob Chemother
. 2008;62:1-4; 2. Swain MG, et al.
Gastroenterology.
2010;139:1593–1601.
cccDNA=covalently closed circular DNA; HBV=hepatitis B virus.
HIV
HBV
Treatment Goal:
Life-long viral suppression
1
Treatment Goal:
Life-long viral suppression
1
HIV
HBV
HCV
Treatment Goal:
SVR
1
HCV
Majority of patients who achieve an SVR do not experience viral recurrence
2
Host Cell
Nucleus
Proviral DNA
Host DNA
Host Cell
Nucleus
cccDNA
Host DNA
Host Cell
Nucleus
Viral RNA
Host DNA
Treatment Goal in HCV Is SVR Slide34
34
SVR
ETR
†
RVR
Weeks After Start of Therapy
HCV RNA (log
10
IU/mL)
Relapse
EVR
Partial Response
Virologic Response to Therapy
Adapted from Ghany MG, et al.
Hepatology
. 2009;49:1335-1374.
†Shown for 48-week fixed-treatment course; follow stopping rules for treatment.
Null Response
UndetectableSlide35
35
Sustained
Virologic
Response (SVR) Achieved After Treatment Is Durable
SVR = HCV RNA negative (by a sensitive assay, <25 IU/mL) at
12 weeks after cessation of treatment
1
99% of patients who achieved an SVR had undetectable levels of HCV RNA in serum samples throughout the follow-up period
2,*
“These data suggest that the recurrence of HCV RNA is extremely rare in patients who achieve an SVR, and it now appears likely that such patients may be considered “cured” from a
virologic
standpoint”
2
For patients with cirrhosis, current guidelines recommend monitoring those who have achieved an SVR at 6- or 12-month intervals for the development of HCC
1
*After treatment with peginterferon alfa-2a ± ribavirin; mean follow-up, 3.9 years (range, 0.8–7.1 years).
1. Ghany MG, et al.
Hepatology
. 2009;49:1335-1374; 2. Swain MG, et al.
Gastroenterology.
2010;139:1593–1601.Slide36
36
SVR and All-cause Mortality in CHC Patients with Advanced Fibrosis
Baseline factors significantly associated with
all-cause mortality:
Older age
GT 3 (2-fold increase in mortality and HCC)
Higher Ishak fibrosis score
Diabetes
Severe alcohol use
SVR patients
Non-SVR patients
10-year cumulative
occurrence rate (%)
8.9
26.0
1.9
27.4
5.1
21.8
2.1
29.9
25
20
15
10
5
0
30
All-cause
mortality
Liver-related
mortality or
liver transplant
HCC
Liver failure
530 patients followed for a median of 8.4 years
Van der Meer A,
et al. JAMA
2012; 308:2584‒2593.Slide37
37
Years
Years
Years
0
1
2
3
4
5
6
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Cumulative Mortality (%)
Genotype 1
(n=12,166)
SVR
Non-SVR
P
<.
0001
SVR rate: 35%
Genotype 2
(n=2904)
SVR
Non-SVR
P
<.
0001
SVR rate: 72%
Genotype 3
(n=1794)
SVR
Non-SVR
P
<.
0001
SVR rate: 62%
Retrospective
analysis
of
veterans
who
received
pegylated
interferon
plus
ribavirin
at
any
VA
medical
facility
(2001-2008).
SVR=
sustained
virological
response
.
Backus
LI, et al.
Clin
Gastroenterol
Hepatol
. 2011;9:509-516.
SVR Reduced Risk of All-Cause Mortality in a Retrospective VA StudySlide38
38
Achieving SVR Was Associated With a 62-84% Reduction in the Risk of All-Cause Mortality
Saleem
J et al, AASLD 2014; Abstract #44Slide39
39
Achieving SVR Was Associated With a 68-79% Reduction in the Risk of HCC
Saleem
J et al, AASLD 2014; Abstract #44Slide40
40
Achieving SVR Was Associated With a 90% Reduction in the Risk of Liver Transplantation
Saleem
J et al, AASLD 2014; Abstract #44Slide41
41
SVR Was Associated with Improved Quality of Life in a Real-World Clinic Population
A study of community patients from hospitals in Vancouver has shown that sustained responders reported higher scores than treatment failures on each domain of the SF-36 and on utility measures
This analysis was part of a larger study examining the quality of life and economic burden of HCV in community patients recruited from 5 clinical settings in Vancouver, British Columbia, and included a cross-sectional administration of questionnaires with retrospective review of medical records
.
Of these, 235
patients
(133 responders and 102 treatment failures) completed questionnaires at an average of 3.7 years after end of treatment. Patients with advanced liver disease were excluded.
Sustained
responders = undetectable
HCV viral levels 6 months after therapy; treatment
failures = detectable
HCV viremia after therapy, or patients with an end-of-treatment response who relapsed.
MCS = mental
summary score (0-100);
PCS = physical
summary score (0-100). *
P
<.0001;
†
P
<.001;
≠
P
<.01.
John-Baptiste AJ, et al.
Am J Gastroenterol.
2009;104:2439-2448.
Mean Difference
Bodily Pain
General Health
Physical Functioning
Role Physical
Role Emotional
Social Functioning
Vitality
Mental Health
PCS
MCS
SF-36 Scales
*
*
*
†
†
†
†
†
†
≠
Mean difference in scores (SVR
versus
treatment failure)Slide42
42
SVR Was Associated With Improved HRQOL in a Survey of Patients With Advanced Fibrosis or Cirrhosis
Study assessed change from baseline to week 72 in HRQOL and sexual health in patients with advanced fibrosis or cirrhosis in the HALT-C Trial.
HRQOL=Health-related quality of life.
HRQOL was assessed with the 36-item Short Form Health Survey (SF-36), plus 3 additional questions that addressed self-reported sexual functioning, desire, and satisfaction and were hypothesized to measure sexual effects of chronic HCV and its treatment.
Bonkovsky HL, et al.
J Hepatol
. 2007;46:420-431.
HRQOL Scale
Mean Change From BaselineSlide43
43
Mean per-patient-per-month (PPPM) follow-up costs
by treatment history and liver disease severity (2010)
CC = compensated
cirrhosis;
ESLD = end-stage
liver disease;
NCD = noncirrhotic
disease.
Covariates adjusted for in the analysis included age, sex, geographical region, index year, baseline comorbidities, and baseline treatment for HCV.
Gordon SC, et al.
Aliment Pharmacol Ther
. 2013;38:784-793.
Treating HCV Has Been Shown to Reduce Healthcare Costs in the US
HCV-related costs
Medical costs
Total costsSlide44
44
Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting,
April 27-28, 2011, Silver Spring, MD
.
SVR (%)
IFN
6 mos
PegIFN/ RBV
12 mos
IFN
12 mos
IFN/RBV
12 mos
PegIFN
12 mos
2001
1998
2011
Standard
IFN
RBV
PegIFN
1991
DAAs
PegIFN/
RBV/
DAA
IFN/RBV
6 mos
6
16
34
42
39
55
70+
0
20
40
60
80
100
DAA
+/-
RBV
90+
2017
The Good NewsSlide45
45
Multi-targeted Approach for Treatment:
Approved Protease, Polymerase and NS5A Inhibitors
Simeprevir
Paritaprevir
Grazoprevir
Asunaprevir
Sofosbuvir
Dasabuvir
B
eclabuvir
Ledipasvir
Ombitasvir
Daclatasvir
Elbasvir
Adapted from McGovern B, Abu
Dayyeh
B, and Chung RT.
Hepatology
. 2008; 48:1700-12
*agents in red will be briefly discussed but are investigational in the USSlide46
46
DAAs in Late-Stage Clinical Development for Chronic HCV Infection
NS3
/
4A
Protease
Inhibitors
Nucleotide
NS5B
Polymerase Inhibitors
Non-Nucleoside
NS5B
Polymerase Inhibitors
NS5A
Replication Complex Inhibitors
Cyclophilin Inhibitors
Approved
Simeprevir
Boceprevir
Telaprevir
Paritaprevir/r
Grazoprevir
Sofosbuvir
Dasabuvir
Ledipasvir
Ombitasvir
Daclatasvir
Elbasvir
Phase 3
Asunaprevir
ABT-493
GS-9857
Beclabuvir
Velpatasvir
ABT-530
Phase 2
Vedroprevir
Sovaprevir
ACH-3422
MK-3682
ALS-335
TMC647055
Odalasvir
MK-8408
PPI-668
SCY
-635
Not all inclusive.Slide47
47
Genotype
1a
Genotype
1b
No Cirrhosis
With Cirrhosis*
No Cirrhosis
With Cirrhosis*
Ledipasvir/sofosbuvir (90/400 mg qd)
12
12
12
12
Elbasvir/grazoprevir (50/100 mg)
12
†
12
†
12
12
Ombitasvir/paritaprevir/r (25/150/100 mg qd)
+ dasabuvir (250 mg bid)
+
RBV
12
(with RBV)
NR
12
(no RBV)
12
(no RBV)
Sofosbuvir (400 mg qd) + simeprevir (150 mg qd)
12
NR
12
NR
Daclatasvir (60 mg qd)
‡
+ sofosbuvir (400 mg qd)
12
NR
12
NR
AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 1
Duration of Therapy (weeks)
*Compensated cirrhosis.
†
No baseline high fold-change NS5A RAVs for elbasvir (includes
M28A
/G/T,
Q30D
/E/H/G/K/L/R,
L31F
/M/V,
Y93C
/H/N/S).
‡
Dose may need to increase or decrease when used concomitantly with cytochrome
P450
3A
/4 inducers and inhibitors, respectively.
NR: not an AASLD-IDSA recommended regimen for this patient type.
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.Slide48
48
General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 1 Patients
Treatment-Naïve, No Cirrhosis
SVR12
Rate
Relapse Rate
Discontinuations
Due to Adverse Events
Ledipasvir/sofosbuvir
8 weeks
12 weeks
97
(119/123)
97
(385/395)
2
(2/123)
<1
(3/395)
0
(0/123)
<1
(2/395)
Elbasvir/grazoprevir
12 weeks (non-cirrhotics and cirrhotics combined)*
97
(271/279)
*
4
(10/279)
*
1
(4/279)
*
Ombitasvir/paritaprevir/r + dasabuvir
Genotype 1a (with RBV), 12 weeks
Genotype 1b (no RBV), 12 weeks
97
(97/100)
99 (207/209)1 (1/98)0 (0/207)0 (0/98)0 (0/207)
Simeprevir + sofosbuvir 12 weeks
97
(112/115)
3
†
(4/154)
0
(0/115)
Daclatasvir
+ sofosbuvir
12 weeks
98
(111/113)
<1
(1/113)
0
(0/113)
Ledipasvir/sofosbuvir: 8 weeks (ION-3, pre-treatment HCV RNA <6 M IU/mL), 12 weeks (ION-3 and ION-1).
Elbasvir/grazoprevir: 12 weeks (C-EDGE, C-WORTHY).
Ombitasvir/paritaprevir/r + dasabuvir: genotype 1a (PEARL-IV), genotype 1b (PEARL-III).
Simeprevir + sofosbuvir: 12 weeks (OPTIMIST-1 [SVR12 rate for genotype
1a+Q80K
: 96%, 44/46]).
Daclatasvir + sofosbuvir (not FDA approved for genotype 1): 12 weeks (study 040 and ALLY-2).
*Genotype 1a: no baseline high fold-change NS5A RAVs for elbasvir (SVR12 rate for genotype 1a + these RAVs: 22%, 2/9).
†
Includes treatment-naïve and treatment-experienced patients.Kowdley KV, et al. N Engl J Med.
2014;370:1879-1888; Afdhal N, et al. N Engl J Med. 2014;370:1889-1898; Zeuzem S, et al. Ann Intern Med. 2015; 163:1-13; Sulkowski MS, et al. Lancet. 2015;385:1087-1097; Ferenci P, et al. N Engl J Med. 2014;370:1983-1992; Kwo P, et al.
Hepatology. 2016; Jan 22. [Epub ahead of print]; Sulkowski MS, et al. N Engl J Med. 2014;370:211-221; Wyles DL, et al. N Engl J Med. 2015;373:714-725.
Percent (n/N)Slide49
49
General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 1 Patients
Treatment-Naïve, Compensated Cirrhosis
SVR12
Rate
Relapse Rate
Discontinuations
Due to Adverse Events
Ledipasvir/sofosbuvir
12 weeks
94
(32/34)
3
(1/34)
0
(0/34)
Elbasvir/grazoprevir
12 weeks*
97
(96/99)
1
(1/99)
2
(2/99)
Ombitasvir/paritaprevir/r + dasabuvir
Genotype 1b (no RBV), 12 weeks
100
(22/22)
0
(0/22)
0
(0/22)
Ledipasvir/sofosbuvir: 12 weeks (ION-3 and ION-1).
Elbasvir/grazoprevir: 12 weeks (C-EDGE, C-WORTHY).
Ombitasvir/paritaprevir/r + dasabuvir: genotype 1b (TURQUOISE-II).
*Genotype 1a: no baseline high fold-change NS5A RAVs for elbasvir.
Afdhal
N, et al.
N Engl J Med.
2014;370:1889-1898; Lawitz E, et al.
Lancet
. 2015;385:1075-1086;
Poordad F, et al.
N Engl J Med
. 2014;370:1973-1982;
AASLD-IDSA. http://
www.hcvguidelines.org
/full-report-view. February 24, 2016.
Percent (n/N)Slide50
50
No
Cirrhosis
Compensated
Cirrhosis
Sofosbuvir (400 mg qd) + RBV
12
16-24
Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd)
Not eligible to receive RBV
12
16-24
AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 2
Duration of Therapy (weeks)
*Dose may need to increase or decrease when used concomitantly with cytochrome
P450
3A
/4 inducers and inhibitors, respectively.
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.Slide51
51
No
Cirrhosis
Compensated
Cirrhosis
Sofosbuvir (400 mg qd) + PR
Eligible to receive pegIFN
12
12
Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd)
+
RBV
12
(no RBV)
24
(
+
RBV)
AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 3
Duration of Therapy (weeks)
*Dose may need to increase or decrease when used concomitantly with cytochrome
P450
3A
/4 inducers and inhibitors, respectively.
PR: pegIFN/RBV.
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.Slide52
52
General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 3 Patients
Foster GR, et al.
Gastroenterology
. 2015;149:1462-1470.
Nelson DR, et al.
Hepatology.
2015;61:1127-1135.
Hezode
C, et al.
Hepatology.
2015;62(suppl
S1
):
314A
. Abstract 206.
Sofosbuvir + PR: 12 weeks (FISSION and VALENCE).
Daclatasvir + sofosbuvir: 12 weeks (ALLY-3); 24 weeks (French Compassionate Use Program).
*Includes genotype 3 treatment-naïve/experienced patients regardless of cirrhosis status.
†
Also includes genotype 3, treatment-naive cirrhotics and genotype 2, treatment-naive cohort.
‡
Combined data from the 12- and 24-week treatment groups.
Treatment-Naïve, No Cirrhosis
SVR12
Rate
Relapse Rate
Discontinuations
Due to Adverse Events
Sofosbuvir + PR
12 weeks
96
(68/71)
5*
(9/181)
1
†
(1/94)
Daclatasvir + sofosbuvir 12 weeks97 (73/75)3 (2/75)
0
(0/75)
Daclatasvir
+ sofosbuvir
24 weeks (
+
RBV)
85
(155/183)
7*
(16/219)
<1*
‡
(3/468)
Percent (n/N)
Treatment-Naïve, Compensated CirrhosisSlide53
53
No
Cirrhosis
Compensated
Cirrhosis
Ledipasvir/sofosbuvir (90/400 mg qd)
12
12
Elbasvir/grazoprevir (50/100 mg)
12
12
Ombitasvir/paritaprevir/r (25/150/100 mg qd) + RBV
12
12
AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 4
Duration of Therapy (weeks)
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.Slide54
54
General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 4 Patients
Treatment-Naïve, Treatment-Experienced
SVR12
Rate
Relapse Rate
Discontinuations
Due to Adverse Events
Ledipasvir/sofosbuvir 12 weeks
No cirrhosis
Compensated cirrhosis
93
(39/42)
100
(10/10)
7
(3/42)
0
(0/10)
0
(0/42)
0
(0/10)
Elbasvir/grazoprevir 12 weeks
No cirrhosis
Compensated cirrhosis
96
(54/56)
100
(6/6)
2
(1/56)
0
(0/10)
0
(0/56)
0
(0/6)
Ombitasvir/paritaprevir/r + RBV
12 weeks
No cirrhosis
Compensated cirrhosis
100
(91/91)
96
(52/54)
0
(91/91)
0
(0/52)
0
(0/91)
0
(0/52)
Ledipasvir/sofosbuvir: 12 weeks (study 1119 and ION-4 [no cirrhosis]).
Elbasvir/grazoprevir: 12 weeks (pooled analysis of phase 2/3 studies).
Ombitasvir/paritaprevir/r + RBV: 12 weeks (PEARL-I [non-cirrhotics] and AGATE-1[cirrhotics]).
*Includes cirrhotics/non-cirrhotics.
Abergel
A, et al.
J Hepatol.
2015;62(suppl 2):
S219
. Abstract
O056
;
Naggie S, et al.
N Engl J Med
. 2015;373:705-713; Asselah T, et al. Hepatology. 2015;62(suppl S1):340A. Abstract 251; Hezode
C, et al. Lancet. 2015;385:2502-2509; Asselah T, et al.
J Hepatol. 2016;64(suppl 2):S827. Abstract SAT-278.Percent (n/N)Slide55
55
No
Cirrhosis
Compensated
Cirrhosis
Ledipasvir/sofosbuvir (90/400 mg qd)
12
12
AASLD-IDSA: Recommended HCV Regimens for Treatment-Naïve, Genotype 5 and 6
Duration of Therapy (weeks)
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.Slide56
56
General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 5 and 6 Patients
Genotype 5: Treatment-Naïve, Treatment-Experienced
Ledipasvir/sofosbuvir (12 weeks): genotype 5 (study 1119) and genotype 6 (ELECTRON).
Abergel
A, et al.
Lancet Infect Dis.
2016;16:459-464.
Gane EJ, et al.
Gastroenterology
. 2015;149:1454-1461.
Percent (n/N)
SVR12
Rate
Relapse Rate
Discontinuations
Due to Adverse Events
Ledipasvir/sofosbuvir 12 weeks
No cirrhosis
Compensated cirrhosis
97
(31/32)
89
(8/9)
3
(1/32)
11
(1/9)
0
(0/32)
0
(0/9)
Ledipasvir/sofosbuvir 12 weeks
No cirrhosis/compensated cirrhosis
96
(24/25)
4
(1/25)
0
(0/25)
Genotype 6: Treatment-Naïve, Treatment-ExperiencedSlide57
57
AASLD-IDSA: Alternative HCV Regimens for Treatment-Naïve Patients
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.
Genotype
No Cirrhosis
Compensated Cirrhosis
1a
None
Ombitasvir/paritaprevir/r (25/150/100 mg qd) + dasabuvir (250 mg bid) + RBV for 24 weeks
Elbasvir/grazoprevir* (50/100 mg) + RBV for 16 weeks
Sofosbuvir (400 mg qd) + simeprevir
†
(150 mg qd)
+
RBV for 24 weeks
Daclatasvir (60 mg qd)
‡
+ sofosbuvir (400 mg qd)
+
RBV for 24 weeks
1b
None
Sofosbuvir (400 mg qd) + simeprevir (150 mg qd)
+
RBV for 24 weeks
Daclatasvir (60 mg qd)
‡
+ sofosbuvir (400 mg qd)
+
RBV for 24 weeks
2
None
None
3
Sofosbuvir (400 mg qd) + RBV for 24 weeks (daclatasvir and INF ineligible, with/without compensated cirrhosis)
4
Sofosbuvir (400 mg qd) + PR for 12 weeks (INF eligible, with/without compensated cirrhosis)
5 and 6
Sofosbuvir (400 mg qd) + PR for 12 weeks (INF eligible, with/without compensated cirrhosis)
*
With baseline high fold-change NS5A RAVs for elbasvir (includes
M28A
/G/T,
Q30D
/E/H/G/K/L/R,
L31F
/M/V,
Y93C
/H/N/S).
†
No baseline
Q80K
detected.
‡
Dose may need to increase or decrease when used concomitantly with cytochrome
P450
3A
/4 inducers and inhibitors, respectively.
PR: pegIFN/RBV.
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).Slide58
58
Genotype
1a
Genotype
1b
No Cirrhosis
With Cirrhosis*
No Cirrhosis
With Cirrhosis*
Ledipasvir/sofosbuvir (90/400 mg qd)
+
RBV
12
(no RBV)
12
(with RBV)
24
(no RBV)
12
(no RBV)
12
(with RBV)
24
(no RBV)
Elbasvir/grazoprevir (50/100 mg)
12
†
12
†
12
12
Ombitasvir/paritaprevir/r (25/150/100 mg qd)
+ dasabuvir (250 mg bid)
+
RBV
12
(with RBV)
NR
12
(no RBV)
12
(no RBV)
Sofosbuvir (400 mg qd) + simeprevir (150 mg qd)
12
NR
12
NR
Daclatasvir (60 mg qd)
‡
+ sofosbuvir (400 mg qd)
12
NR
12
NR
AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 1
Duration of Therapy (weeks)
*Compensated cirrhosis.
†
No baseline high fold-change NS5A RAVs for elbasvir (includes
M28A
/G/T,
Q30D
/E/H/G/K/L/R,
L31F
/M/V,
Y93C
/H/N/S).
‡
Dose may need to increase or decrease when used concomitantly with cytochrome
P450
3A
/4 inducers and inhibitors, respectively.
PR: pegIFN/RBV.
NR: not an AASLD-IDSA recommended regimen for this patient type.
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.Slide59
59
General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 1 Patients
Prior PR Failure, No Cirrhosis
SVR12
Rate
Relapse Rate
Discontinuations
Due to Adverse Events
Ledipasvir/sofosbuvir
12 weeks
95
(83/87)
5
(4/86)
0
(0/86)
Elbasvir/grazoprevir
12 weeks (no cirrhosis and cirrhosis combined)*
94
(90/96)
*
5
(15/96)
*
1
(1/96)
*
Ombitasvir/paritaprevir/r + dasabuvir
Genotype 1a (with RBV), 12 weeks
Genotype 1b (no RBV), 12 weeks
96
(286/297)
100
(91/91)
2
(7/293)
0
(0/91)
1
(3/297)0 (0/91)Simeprevir + sofosbuvir 12 weeks95 (38/40)3
(4/154)
0
(0/155)
Daclatasvir
+ sofosbuvir
12 weeks
100
†
(20/20)
--
--
Ledipasvir/sofosbuvir: 12 weeks (ION-2).
Elbasvir/grazoprevir: 12 weeks (C-EDGE-
TE
from full prescribing information).
Ombitasvir/paritaprevir/r + dasabuvir: 12 weeks genotype 1a (SAPPHIRE-II) and genotype 1b (PEARL-II).
Simeprevir + sofosbuvir: 12 weeks (OPTIMIST-1 [SVR12 rate for genotype
1a+Q80K
: 96%, 44/46]).
Daclatasvir + sofosbuvir (not FDA approved for genotype 1): 12 weeks (
HEPATHER
).
*Genotype 1a: no baseline high fold-change NS5A RAVs for elbasvir (SVR12 rate for genotype 1a + these RAVs: 64%, 9/14).
†
Includes treatment-naïve and treatment-experienced patients.
Afdhal N, et al.
N Engl J Med. 2014;370:1483-1493; Elbasvir/grazoprevir full prescribing information; Zeuzem S, et al. N Engl J Med. 2014;370:1604-1616; Andreone P, et al. Gastroenterology
. 2014;147:359-365; Kwo P, et al. Hepatology. 2016;Jan 22. [Epub ahead of print]; Pol S, et al. J Hepatol. 2015;62(suppl 2):258. Abstract LO3.
Percent (n/N)Slide60
60
General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 1 Patients
Prior PR Failure, Compensated Cirrhosis
SVR12
Rate
Relapse Rate
Discontinuations
Due to Adverse Events
Ledipasvir/sofosbuvir
12 weeks (with RBV)
24 weeks (no RBV)
94
(93/99)
98
(97/99)
6
(6/99)
3
(3/99)
0
(0/99)
0
(0/99)
Elbasvir/grazoprevir
12 weeks (no cirrhosis and cirrhosis combined)*
94
(90/96)
*
5
(15/96)
*
1
(1/96)
*
Ombitasvir/paritaprevir/r + dasabuvir
Genotype 1b (no RBV), 12 weeks
98
(45/46)
1.5†
(1/68)2† (2/172)Ledipasvir/sofosbuvir: 12 weeks (ION-2 and SIRIUS).Elbasvir/grazoprevir: 12 weeks (C-EDGE-TE from full prescribing information).
Ombitasvir/paritaprevir/r + dasabuvir: genotype 1b (TURQUOISE-II).*Genotype 1a: no baseline high fold-change NS5A RAVs for elbasvir.
Percent (n/N)
Afdhal
N, et al.
N Engl J Med.
2014;370:1483-1493;
Bourlière
P, et al.
Lancet Infect Dis
. 2015;15:397-404;
Elbasvir/grazoprevir full prescribing
information;
Poordad F, et al.
N Engl J Med
. 2014;370:1973-1982;
Pol S, et al.
J Hepatol.
2015;62(suppl 2):258. Abstract
LO3
.Slide61
61
No
Cirrhosis
Compensated
Cirrhosis
Sofosbuvir (400 mg qd) + RBV
12
16-24
Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd)
Not eligible to receive RBV
12
16-24
AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 2
Duration of Therapy (weeks)
*Dose may need to increase or decrease when used concomitantly with cytochrome
P450
3A
/4 inducers and inhibitors, respectively.
PR: pegIFN/RBV.
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.Slide62
62
No
Cirrhosis
Compensated
Cirrhosis
Sofosbuvir (400 mg qd) + PR
Eligible to receive pegIFN
12
12
Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd)
+
RBV
12
(no RBV)
24
(
+
RBV)
(IFN ineligible)
AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 3
Duration of Therapy (weeks)
*Dose may need to increase or decrease when used concomitantly with cytochrome
P450
3A
/4 inducers and inhibitors, respectively.
PR: pegIFN/RBV.
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.Slide63
63
General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 3 Patients
Foster GR, et al.
Gastroenterology
. 2015;149:1462-1470.
Nelson DR, et al.
Hepatology.
2015;61:1127-1135.
Hezode
C, et al.
Hepatology.
2015;62(suppl
S1
):
314A
. Abstract 206.
Sofosbuvir + PR: 12 weeks (BOSON).
Daclatasvir + sofosbuvir: 12 weeks (ALLY-3); 24 weeks (French Compassionate Use Program).
*Includes genotype 3 cohort (regardless of prior treatment experience and cirrhosis status).
†
Includes genotype 2 and 3 cohorts (regardless of prior treatment experience and cirrhosis status).
‡
Includes treatment-naïve and treatment-experienced patients.
§
Combined data from the 12- and 24-week treatment groups.
SVR12
Rate
Relapse Rate
Discontinuations
Due to Adverse Events
Sofosbuvir + PR
12 weeks
94
(49/52)
5*
(9/181)
1
†
(1/103)Daclatasvir + sofosbuvir 12 weeks94 (32/33)3 (2/75)0 (0/75)
Sofosbuvir + PR
12 weeks
86
(30/35)
5*
(9/181)
1
†
(1/103)
Daclatasvir
+ sofosbuvir
24 weeks (
+
RBV)
85
‡
(155/183)
7*
(16/219)
<1*
§
(3/468)
Percent (n/N)
Prior PR Failure, Non-Cirrhotic
Prior PR Failure, Compensated CirrhosisSlide64
64
No
Cirrhosis
Compensated
Cirrhosis
Ledipasvir/sofosbuvir (90/400 mg qd)
+
RBV
12
12
(with RBV)
24
(no RBV)
Elbasvir/grazoprevir (50/100 mg)
+
RBV
Prior PR relapse
Prior PR failure
12
(no RBV)
16
(with RBV)
12
(no
RBV)
16
(with
RBV)
Ombitasvir/paritaprevir/r (25/150/100 mg qd) + RBV
12
12
AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 4
Duration of Therapy (weeks)
PR: pegIFN/RBV.
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.Slide65
65
General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 4 Patients
Treatment-Naïve, Treatment-Experienced
SVR12
Rate
Relapse Rate
Discontinuations
Due to Adverse Events
Ledipasvir/sofosbuvir 12 weeks
No cirrhosis
Compensated cirrhosis
93
(39/42)
100
(10/10)
7
(3/42)
0
(0/10)
0
(0/42)
0
(0/10)
Elbasvir/grazoprevir*
Prior PR relapse, 12 weeks
(no RBV)
Prior PR failure, 16 weeks (with RBV)
100
(2/2)
100
(5/5)
0
(0/2)
0
(0/5)
0
(0/2)
0
(0/5)
Ombitasvir/paritaprevir/r + RBV
12 weeks
No cirrhosis
Compensated cirrhosis
100
(91/91)
96
(52/54)
0
(91/91)
0
(0/52)
0
(0/91)
0
(0/52)
Ledipasvir/sofosbuvir: 12 weeks (study 1119 and ION-4 [no cirrhosis]).
Elbasvir/grazoprevir: 12 weeks (pooled analysis of phase 2/3 studies).
Ombitasvir/paritaprevir/r + RBV: 12 weeks (PEARL-I [non-cirrhotics] and AGATE-1[cirrhotics]).
*Includes cirrhotics/non-cirrhotics.
Abergel
A, et al.
J Hepatol.
2015;62(suppl 2):
S219
. Abstract
O056
;
Naggie S, et al.
N Engl J Med. 2015;373:705-713; Asselah T, et al. Hepatology. 2015;62(suppl S1):340A
. Abstract 251; Hezode C, et al. Lancet. 2015;385:2502-2509; Asselah
T, et al. J Hepatol. 2016;64(suppl 2):S827. Abstract SAT-278.Percent (n/N)Slide66
66
No
Cirrhosis
Compensated
Cirrhosis
Ledipasvir/sofosbuvir (90/400 mg qd)
12
12
AASLD-IDSA: Recommended HCV Regimens for Prior PR Failure, Genotype 5 and 6
Duration of Therapy (weeks)
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.
PR: pegIFN/RBV.
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).Slide67
67
General Outcomes With AASLD-IDSA Recommended HCV Regimens for Genotype 5 and 6 Patients
Genotype 5: Treatment-Naïve, Treatment-Experienced
Ledipasvir/sofosbuvir (12 weeks): genotype 5 (study 1119) and genotype 6 (ELECTRON).
Percent (n/N)
SVR12
Rate
Relapse Rate
Discontinuations
Due to Adverse Events
Ledipasvir/sofosbuvir 12 weeks
No cirrhosis
Compensated cirrhosis
97
(31/32)
89
(8/9)
3
(1/32)
11
(1/9)
0
(0/32)
0
(0/9)
Ledipasvir/sofosbuvir 12 weeks
No cirrhosis/compensated cirrhosis
96
(24/25)
4
(1/25)
0
(0/25)
Genotype 6: Treatment-Naïve, Treatment-Experienced
Abergel
A, et al.
Lancet Infect Dis.
2016;16:459-464.
Gane EJ, et al.
Gastroenterology
. 2015;149:1454-1461.Slide68
68
AASLD-IDSA: Alternative HCV Regimens for Prior PR Failure
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.
Genotype
No Cirrhosis
Compensated Cirrhosis
1a
None
Ombitasvir/paritaprevir/r (25/150/100 mg qd) + dasabuvir (250 mg bid) + RBV for 24 weeks
Elbasvir/grazoprevir* (50/100 mg) + RBV for 16 weeks
Sofosbuvir (400 mg qd) + simeprevir
†
(150 mg qd)
+
RBV for 24 weeks
Daclatasvir (60 mg qd)
‡
+ sofosbuvir (400 mg qd)
+
RBV for 24 weeks
1b
None
Sofosbuvir (400 mg qd) + simeprevir (150 mg qd)
+
RBV for 24 weeks
Daclatasvir (60 mg qd)
‡
+ sofosbuvir (400 mg qd)
+
RBV for 24 weeks
2
None
Sofosbuvir (400 mg qd) + PR for 12 weeks (IFN eligible)
3
None
None
4
Sofosbuvir (400 mg qd) + PR for 12 weeks (IFN eligible, no cirrhosis and compensated cirrhosis)
Sofosbuvir (400 mg qd) + RBV for 24 weeks (IFN ineligible, no cirrhosis and compensated cirrhosis)
5 and 6
Sofosbuvir (400 mg qd) + PR for 12 weeks (INF eligible, with/without compensated cirrhosis)
*
With baseline high fold-change NS5A RAVs for elbasvir (includes
M28A
/G/T,
Q30D
/E/H/G/K/L/R,
L31F
/M/V,
Y93C
/H/N/S).
†
No baseline
Q80K
detected.
‡
Dose may need to increase or decrease when used concomitantly with cytochrome
P450
3A
/4 inducers and inhibitors, respectively.
PR: pegIFN/RBV.
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).Slide69
69
No Cirrhosis
Compensated Cirrhosis
Ledipasvir/sofosbuvir (90/400 mg qd)
+
RBV
12
12
(with RBV)
24
(no RBV)
Elbasvir/grazoprevir (50/100 mg) + RBV
Genotype 1b
Genotype 1a based on presence of baseline
high fold-change NS5A RAVs for elbasvir
No
Yes
12
12
16
12
12
16
Daclatasvir (60 mg qd)
‡
+ sofosbuvir (400 mg qd)
12
24
(
+
RBV)
AASLD-IDSA: Recommended HCV Regimens for Prior NS3 PI +
PegIFN
/RBV Failure, Genotype 1
Duration of Therapy (weeks)
*
Dose may need to increase or decrease when used concomitantly with cytochrome
P450
3A
/4 inducers and inhibitors, respectively.
NS3 PIs: telaprevir, boceprevir, or simeprevir.
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).
Baseline high fold-change NS5A RAVs for elbasvir (includes
M28A
/G/T,
Q30D
/E/H/G/K/L/R,
L31F
/M/V,
Y93C
/H/N/S).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.Slide70
70
No Cirrhosis
Compensated Cirrhosis
Ledipasvir/sofosbuvir (90/400 mg qd)
+ RBV
12
24
AASLD-IDSA: Recommended HCV Regimens for
Prior Sofosbuvir + RBV
+
PegIFN Failure, Genotype 1
Duration of Therapy (weeks)
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.Slide71
71
Duration of Therapy (weeks)
No Cirrhosis
Compensated Cirrhosis
Sofosbuvir (400 mg qd) + PR
IFN eligible
12
12
Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd)
+
RBV
Not eligible to receive pegIFN and/or RBV
24
24
AASLD-IDSA: Recommended HCV Regimens for Prior
Sofosbuvir
+ RBV Failure, Genotype 2 and 3
*
Dose may need to increase or decrease when used concomitantly with cytochrome
P450
3A
/4 inducers and inhibitors, respectively.
PR: pegIFN/RBV.
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.Slide72
72
AASLD-IDSA Recommendations for Genotype 1 Patients Who Failed Other DAA-Based Regimens
Prior
simeprevir
+
sofosbuvir
or HCV NS5A inhibitor-based regimen failures
For patients without an urgent need for treatment, deferral of retreatment is recommended pending the availability of additional data
Compensated cirrhosis or those with an urgent need for retreatment
Test for RAVs to determine susceptibility status to NS3 PIs and NS5A inhibitors
Adjust retreatment regimen based on RAV testing results
When using nucleotide-based (
eg
,
sofosbuvir
) dual therapy, a treatment duration of 24 weeks with weight-based RBV is recommended
If available, nucleotide-based (
eg
,
sofosbuvir
) triple or quadruple DAA regimens may be considered (with RBV* for 12 to 24 weeks is recommended)
*Unless contraindicated.
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February
24
,
2016
.Slide73
73
Long-Term Follow-Up of HCV Patients Treated With DAA Regimens
Prospective, observational cohorts
SVR Registry: SVR12 achievers (n=5433)
Median follow-up: 71 weeks
Sequence Registry: virologic failure patients (n=536)
Median follow-up: 44 weeks
Maintained SVR: 99.7% (5414/5433)
Late virologic relapse: 0.1%
HCV reinfection: 0.2%
Low rates of clinical disease progression
Incidence of HCC
SVR registry: 0.3% (16/5433)
Sequence registry: 0.9% (5/536)
Lawitz EJ, et al.
J Hepatol.
2016;64(suppl 2):
S612-S613
. Abstract FRI-166.
SVR
(n=5433)
Sequence
(n=563)
Median age (years)
54
54
Male (%)
63
78
White (%)
85
84
Cirrhotics (%)
20
22
HCV genotype (%)
1
2
3
4 5 66710203<1<1
62
5
32
<1
<1
0
Registry CharacteristicsSlide74
74
Considerations for Follow-Up of SVR Patients
Serfaty
L, et al.
Liver Int
. 2016;36(suppl
S1
):67-71.
SVR12
(baseline
F0
/
F1
)
SVR12
(baseline
F2
/
F3
)
SVR12
(baseline
F4
[cirrhosis])
Post-SVR
Week 48
Post-SVR
Week 48
Post-SVR
Week 48
HCV RNA
Non-Invasive Tests
(
F0
/
F1
)
HCV RNA
Non-Invasive Tests(F2/F3)HCV RNAPWID, MSMAlcohol, Obesity, DiabetesHCV RNAEvery 12 MonthsNon-Invasive TestsEvery 12 MonthsLifestyle ChangesDiabetes ControlLiver Biopsy ifElevated ALT/AST
Liver UltrasoundEvery 6 MonthsNo
YesSlide75
75
Strategies To Advance HCV Patient Care
75
PATIENT IDENTIFICATION
SPECIALIST
REFERRAL
HCV DISEASE
MANAGEMENT
Outreach & Awareness
- Need For:
Patient Awareness regarding risk factors & testing
Provider education & awareness regarding HCV testing
Diagnosis
-
Need For:
HCV Testing Protocols
Clearly defined roles & responsibilities for HCV testing among providers
Patient education & engagement upon diagnosis
Care Coordination
- Need For:
Appropriate link to quality care – “Linkage To C Care”
Improved data sharing & communication between PCP & specialist
Patient Stratification
- Need For:
Provider understanding of benchmarks to ensure appropriate management
CLINICAL – HCV genotype, fibrosis scores, comorbidities
SOCIOECONOMIC – Health literacy
Managing Patients
-
Need For:
HCV care management protocols/AASLD Guidelines
Clearly defined roles & responsibilities for HCV management
Patient involvement to improve adherence & treatment success Slide76
76
HepCure Alliance Vision
Educate HCPs on the importance of HCV and their role in the care continuum
Implement rapid testing/screening protocols to increase the number of identified HCV patient
Increase the number of HCV Ab [+] patients that go on for PCR testing & decrease the fall off rates
Increase the number of diagnosed patients linked to care & decrease the fall off ratesSlide77
PCP HCV Screening, Referral & Treatment
Primary Care Visit
Birth Age Cohort – 1945-65
Risk Factors
Abnormal LFT
HCV
antibody
OraQuick
or Phlebotomy
NEGATIVE
No Referral
POSITIVE
HCV RNA PCR
Quantitative
HCV Genotype
Hepatitis B Surface antigen
Hepatitis B Surface Antibody
Hepatitis B Core Total Antibody
Hepatitis A Total Antibody
HIV Antibody
Abdominal Ultrasound &
Fibroscan
Hepatitis A & B Vaccination
Alcohol Abstinence Counselling
Risk Factors
Past or current injection drug use
Recipients of clotting factors (prior 1987)
Chronic hemodialysis
Persistently abnormal ALT
Recipients of transfusions or organ transplants [prior 1992]
Persons with recognized exposures (needle-sticks, mucosal exposures)
HIV-infected persons
Birth to an infected mother
REFER TO
GI/HEPATOLOGY
PRIMARY CARE PROVIDER TREATMENT PER HCV PROTOCOLSlide78
78
EHCO Model: HCV Treatment by Primary Care Providers
Retrospective analysis (2012-2015)
Academic/
speciality
sites (n=6)
Multiple ECHO sites (PCP and subspecialist)
Arizona, New Mexico, Oklahoma, Texas, Utah, Washington
Demographics of patients are similar, except for race and treatment history
More treatment-experienced, genotype 1 and 3 patients were treated by specialist
Regimens
Genotype 1
Ledipasvir
/
sofosbuvir
+
RBV (8 and 12 weeks)
Simeprevir
+
sofosbuvir
+
RBV (12 weeks)
Genotype 2:
sofosbuvir
+ RBV (12 weeks)
Genotype 3:
sofosbuvir
+ RBV (24 weeks)PCPs were as effective as specialists at treating HCV when using the ECHO model
Georgie
F, et al.
J Hepatol.
2016;64(suppl 2):
S818-S819.
Abstract SAT-260.
SVR12 (%)
97%
98%81%
ECHO Specialty
2
(n=48|82)
3
(n=43|67)
1
(n=150|373)
93%
SVR12 Rates (
mITT
)
89%
82%
GenotypeSlide79
79
ASCEND Study: HCV Treatment by Primary Care Providers (2015)
Multicenter, open-label, phase 4 study (n=600 HCV patients)
Washington, DC (3 community health)
Providers underwent 3-hour training on AASLD-IDSA guidelines
Ledipasvir
/
sofosbuvir
per full prescribing information
Patients
Male (66%), HCV genotype 1a (72%), F3/4 (36%), HIV coinfection (24%)
HCV treatment experienced (18%), HCV RNA >6 million (19%)
Treatment duration
8 (5%), 12 (90%), 24 (5%) weeks
HCV treatment administered independently by PCPs and NPs was safe and equally effective as with experienced specialists
Kattakuzhy
S, et al.
J Hepatol.
2016;64(suppl 2):
S224
.
Abstract
LBP524
.
Specialist: infectious disease or hepatology.
SVR12 (%)
94%
95%
92%
Overall
(n=304)
97%
PCP
(n=60)
NP
(n=79)
Specialist
(n=165)
SVR12 RatesSlide80
80
WHAT’S NEXT?
Lawitz
E, et al. EASL
2016: Abstract PS008.
Poordad
F, et al. EASL 2016: Abstract GS11.Hepatitis B Foundation -
http://www.hepb.org/professionals/hbf_drug_watch.htmwww.cancerresearch.org