Transcript Hepatitis C Presentation

1
LACK OF AWARENESS
LACK OF APPROPRIATE ACTION
1. 35-50% of PCP believe
HCV can be cured
1. 50% PCP consider LFT’s
as their “Initial” screen
2. <10% Aware of DAA’s
and new treatment
regimens
2. <25% pf PCPs order
HCV RNA test
3. 20% Plan to screen all
baby boomers
3. Only 20% of PCP
“Would Definitely”
refer an asymptomatic
patient
Expand Quantitative Landscape Study – Oct 2013 [Gilead Sciences]
2
WHY
Is There
An Urgent
Need For
HCV
Diagnosis
?
WHO
Is Most at
Risk For
HCV and
What Is the
Guidance
on Testing?
HOW
WHAT
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?
3
Aware
Drive
Awareness
of HCV and
Treatment
Actions
Engage
Cultivate
Interest
and Intent
to Learn
Act
Prompt consistent
and Quality
Screening, Diagnosis
and Referral
4
An RNA virus that used to be known as non-A,
non-B hepatitis until it was discovered in 19881
No vaccine available
First therapy approved in 19862
• 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
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.
5
Distribution of HCV Genotypes (GTs) in the US3


Approximately 3.2 million
persons in the United States
have chronic hepatitis C virus
(HCV) infection1,a
Seroprevalence is higher
among2
› Individuals born between
1945-1965 (3.5%)
› Black non-Hispanics (2.2%)
› Males (1.9%)
aThis
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.
6
6



Of people with HIV-1 in the US, about 25% are co-infected with HCV1
About 85% of people with HIV who inject drugs also have HCV infection2
HIV infection in a person who is also infected with HCV results in2
› Higher levels of HCV in the blood
› More rapid progression to HCV-related liver disease
› Increased risk for cirrhosis and HCC
All HIV-infected1
HIV-infected
Injection-drug users2
HCC = hepatocellular carcinoma; HIV = human immunodeficiency virus.
1. Thomas DL. Ann Rev Med. 2008; 59:473-485; 2. Sulkowski MS, Thomas DL. Ann Intern Med. 2013;138:197-207.
7
7
POPULATION STUDIES SHOW A SIGNIFICANT GAP
IN HEPATITIS C CARE IN THE UNITED STATES
US Cascade of Care, 2003-20131
3.5 Million
50%
43%
16%
73% GT 1a2
27% GT 1b2
Chronic HCV
infection
1.
2.
Diagnosed
and aware
Access to
outpatient
care
Prescribed
HCV
treatment
9%
Achieved
sustained
virologic
response
(SVR)
8
79%
Genotype
(GT) 12
Yehia BR, et al. PLoS One. 2014;9:e101554.
Zein NN, et al. Ann Intern Med. 1996;125:634-639.
8
Acute Infection*
Clearance of
HCV RNA
15%-25%
Chronic
Infection
75%-85%
Cirrhosis
10%-20% over
20 years
HCC
1%-4% per year
Decompensated
Cirrhosis
5-yr survival rate 50%
Extrahepatic
Manifestations
*20%-30% of individuals are symptomatic.
HCC=hepatocellular carcinoma.
Adapted from Chen SL, Morgan TR. Int J Med Sci. 2006;3:47-52.
9
Nonmodifiable Host Factors
Older age at infection
• Associated with accelerated cirrhosis development1
Increasing age
(longer duration of infection)
• Associated with accelerated fibrosis progression1
Male gender
• Associated with accelerated fibrosis progression and more
frequent HCC development2,3
IL28B CC allele
• More likely to develop adverse clinical outcomesa but not
associated with fibrosis progression4
Transfusion-associated HCV
• Associated with accelerated progression to cirrhosis
(versus community- or childhood-acquired HCV)5
Hispanic ethnicity
• Higher mortality rates from HCV-related cirrhosis6
• Hispanic ethnicity is an independent risk factor for
HCC-related mortality7
Caucasian
• Increased histologic activity and incidence of cirrhosis
(as compared to blacks)2
aClinical
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.
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.
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Behavioral and Clinical/Laboratory Host Factors
Moderate to high alcohol
consumptiona
• Associated with significant risk of advanced hepatic fibrosis
and mortality (all-cause and liver-related)1,2
Heavy smokingb
• Factor for severe fibrosisc in CHC3
HIV-1 co-infection
• Associated with higher viral load, rapid progression to
cirrhosis, liver failure, and HCC4
HBV co-infection
• Associated with increased risk of HCC5
Iron overload
• Correlated with decompensated cirrhosis, HCC, or death6
Combined obesity and diabetes
mellitus
• Associated with 100-fold increase in risk of HCC
development7
Insulin resistance
• Independent predictor of HCC development8 and associated
with increasing fibrosis9
Hepatic steatosis
• Associated with ≥2-point increase in Ishak fibrosis score10
and HCC development11
Platelet counts, AST/ALT ratio,
bilirubin, and albumin
• Independent predictors of fibrosis progression or clinical
decompensation10
HBV = hepatitis B virus. aModerate and high consumption were defined as 1-19 g/day and ≥30 g/day, respectively.2
bLifetime consumption of ≥20 pack-years. cLiver 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.
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
GT 3 was associated with accelerated fibrosis progression1
›

Patients from the Swiss Hepatitis C Cohort Study enrolled before December 2008 (N=1189)
GT 3 was associated with an increased risk of developing HCC2
›
Retrospective study of patients in the VA HCV Clinical Case Registry, 2000-2009
Progression to fibrosis
stage 3-41
GT 1 or 4 (n=492, ref)
GT 2 (n=65, P=.003)
GT 3 (n=244, P<.001)
1.00
Incident HCC2
GT 1 or 4 (n=630, ref)
GT 2 (n=92, P=.04)
GT 3 (n=342, P<.001)
1.00
0.98
0.90
Proportion Free of HCC
Cumulative Incidence of Fibrosis
Progression
Progression to fibrosis
stage 1-21
0.80
0.70
0.60
0.50
0.40
0.30
0.20
0.96
0.94
0.92
0.90
0.88
0.86
0.84
0.10
0.82
0.00
0.80
0
5
10
15
20
Year
25
30
35
40 0
5
10
15
20
25
30
Year
for prespecified demographic, clinical, and treatment factors.2
HR = hazard ratio; VA = Veterans Administration.
35
40
GT 1 (n=88,348)
GT 2 (n=13,077)
GT 3 (n=8,337)
GT 4 (n=1,082)
N=110,484
Adjusted HRa=1.8 (1.61, 2.03)
0 1
2
3
4
5
6
Year
aAdjusted
1. Bochud PY, et al. J Hepatol. 2009;51:655-666; 2. Kanwal F, et al. Hepatology. 2014;60:98-105.
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7
8
9 10 11
Primary cause of disease among
adults on the liver transplant wait list,
2011
All others
26.4%
Primary cause of disease among
adult liver transplant recipients, 2011
All others
22.3%
HCV
30.1%
Metabolic liver
disease
Acute hepatic
necrosis
HBV
6.0%
Malignancy
2.5%
Acute hepatic
necrosis
2.6%
2.8%
9.0%
Alcoholic liver
disease
23.2%
HCV
23.5%
4.0%
Malignancy
20.9%
9.1%
Cholestatic
disease
Alcoholic
liver disease
17.6%
Cholestatic
disease
Available at: http://srtr.transplant.hrsa.gov/annual_reports/2011/pdf/03_%20liver_12.pdf.
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PROGRESSIVE INCREASE IN INCIDENCE OF
HCV-RELATED CIRRHOSIS AND HCC IN US
Annual Prevalence Rates Between 1996 and 2006 Among HCV-Infected Veterans
5%
18%
Cirrhosis
4%
16%
14%
3%
12%
10%
Decompensated
Cirrhosis
2%
8%
HCC
6%
4%
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
El-Serag HB. Gastroenterology 2012;142:1264–1273.
1%
Hepatocellular Cancer (HCC)
Cirrhosis and
Decompensated Cirrhosis
20%
0%
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Patients often asymptomatic in early stages of infection1

Symptoms may include1










Fever
Fatigue
Loss of appetite
Nausea
Vomiting
Abdominal pain
Dark urine
Grey-colored stools
Jaundice
Joint pain
First symptoms may be those of
extrahepatic manifestations2





Arthralgias
Paresthesias
Myalgias
Pruritus
Sicca syndrome
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.
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Strongly associated
Possibly associated
 Mixed cryoglobulinemia
 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
 Sjögren (sicca) syndrome
 Lymphoproliferative
disorders
 Porphyria cutanea tarda
 Neuropathy
 Membranoproliferative
glomerulonephritis
 Cryoglobulinemic
vasculitis
Adapted from Ali A, Zein NN. Cleve Clin J Med. 2005;72:1005-1008.
16
Mortality Rates in the US,
1999-2007
Rate per 100,000 PY*
7
HIV
6
5
4
Hepatitis C
3
2
1
Hepatitis B
0
Yr
*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.
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HCV Viral Replication Associated
With Higher All-Cause Mortality
All Causes
35
Anti-HCV seropositives, HCV RNA detectable
Anti-HCV seropositives, HCV RNA undetectable
Anti-HCV seronegatives
25
30.1%
P < .001 for comparison among 3 groups
P < .001 for HCV RNA detectable vs undetectable
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15
Property Of BioCentra, LLC
Cumulative Mortality (%)
30
12.8%
12.4%
10
5
0
0
2
4
6
Lee MH, et al. J Infect Dis. 2012;206:469-477.
8
10
12
Follow-up (Yrs)
14
16
18
20
18
18
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
180,000
162,559
150,617
160,000
Number of Persons
162,747
140,000
126,296
No treatment
120,000
25% treated
91,310
100,000
80,000
50% treated
49,013
60,000
75% treated
40,000
All treated
20,000
18,193
0
0
5
25,573
27,175
26,207
24,258
21,994
10
15
20
25
30
Year in Model
Desai et al. AASLD 2013. Abstract 1427
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Health Care Cost
(95% CI)
Health Care Cost (Billion)
Prevalence (Million)
Prevalence
(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.
Razavi H, et al. Hepatology. 2013. Epub ahead of print.
20
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.
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HCV-Related Health Care Costs
by Liver Severity (USD 2010)
3505*
3328*
(10,996)
HCV-Related Costs
(per-patient-per-month)
Non-cirrhotic liver disease (n=41,858)
Compensated cirrhosis (n=3718)
End-stage liver disease (n=8220)
(10,996)
2608*
(10,359)
1060*
(2941)
663*
650
(2714)
(2648)
Total Health
Care Costs
579*
(2815)
467
Total
313 334
(2587) (2674)
Inpatient
Medical Costs
304*
130
(1721)
(587)
404*
183
(847)
(612)
Ambulatory
Pharmacy
Costs
(591)
Numbers in parentheses are +SD. *P<0.001 versus non-cirrhotic liver disease.
Gordon SC, et al. Hepatology. 2012;56:1651-1660.
177*
(444)
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PATIENTS SHOULD BE SCREENED FOR HCV ACCORDING TO
BIRTH COHORT AND RISK FACTORS1,2
PATIENT SCREENING FOR HCV
Birth Cohort Screening
Risk Factor–Based Screening
Persons Born Between
1945 and 19651,2
Important Risk Factors1,2
• 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
• Past or current
injection drug use
• Incarceration
• Receiving a blood
transfusion before
1992
• Getting an
unregulated tattoo
• Long-term
hemodialysis
• Intranasal drug use
• Other percutaneous
exposures
• Being born to an
HCV-infected mother
1.
Smith BD, et al. MMWR Recomm Rep. 2012;61:1-32.
2.
Moyer VA; US Preventive Services Task Force. Ann Intern Med. 2013;159:349-357.
23
Cost Per QALY Saved (Dollars)
With
Treatment
3-Drug
Treatment
With
Treatment
2-Drug
Treatment
*Birth cohort testing, 1945-1965.
2-drug treatment=PegIFN+RBV; 3-drug treatment=PegIFN+RBV+PI.
QALY=quality-adjusted life-year.
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.
24
Anti-HCV
Symptoms +/–
HCV RNA
ALT (U/L)

RNA testing identifies
active disease in HCVseropositive patients
HCV antibodies appear
by
6–8 weeks following
infection1
Titer

ALT
› Can be detected by
EIA2


Serum ALT is not a
reliable indicator of
liver damage1
FDA-approved rapid
point-of-care testing is
available3
ULN
0
1
2
3
4
5
6
1
Months
2
3
Years
Time After Exposure
› OraQuick® HCV Test
ALT=alanine aminotransferase; EIA=enzyme immunoassay; RNA=ribonucleic acid; ULN=upper limit of normal.
Image adapted from MicrobiologyBytes:Virology:HCV1
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.
25
4
Anti-HCV
Antibody
Positive
HCV RNA
Negative
Negative
No Further
Testing
No Active
Disease
HCV Genotype
Positive Consider Liver Biopsy
Vaccinate for HAV / HBV*
*If patient lacks pre-existing antibodies to HAV or HBV.
HAV=hepatitis A virus, HBV=hepatitis B virus.
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
26
27
Appearance
Ishak Description
Ishak METAVIR
Score1 Score2
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
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
Marked bridging (P–P and/or P–C) with
occasional nodules (incomplete cirrhosis)
5
Cirrhosis
6
F2
F3
F4
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.
28
Transient
Elastography
Liver Biopsy
Serum Markers
Methodology
Direct observation
Measures direct and
indirect serum
markers* of fibrosis
Liver stiffness by
detection of
ultrasoundpropagated shear
waves
Liver stiffness by MRI
of vibrationpropagated shear
waves
Accuracy for
detecting cirrhosis
High
Moderate (APRI) to
high (FibroSURETM,
ELF)
High
High
Accuracy for
detecting
intermediate fibrosis
High
Low (APRI) to
moderate
(FibroSURETM, 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 /
29
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.
MRE
30
Sensitivity
(%)*
Specificity
(%)*
PPV
(%)*
NPV
(%)*
Cirrhosis
Discrimination
Fibrosis
Discrimination
AST, ALT
53
100
100
81
+
–
APRI2
AST/platelet count
77
72
70
79
+
+/–
(moderate)
FIBROSpect
II®3,4
HA, TIMP-1, a2macroglobulin
72
74
61
82
+
+
FibroSURETM 5,6
• FibroTest
a2-macroglobulin,
haptoglobin, Apo A1,
GGT, total bilirubin, ALT
84
95
76
91
+
+
HepaScore®7
Age, gender, bilirubin,
GGT, HA, g2macroglobulin
77
70
71
77
+
+
ELF8
HA, N-terminal
propeptide of type III
collagen, TIMP-1
86
62
80
70
+
+
Test
Test Components
AST/ALT ratio1
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.
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.
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To Prevent HCV Transmission
 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”
Additional
Recommendations
 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
*If patient meets generally accepted indications for HCV treatment.
Adapted from Ghany MG, et al. Hepatology. 2009;49:1335-1374.
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HCV
HCV
HBV
HBV
Host Cell
Host Cell
HIV
HIV
Host Cell
Viral RNA
cccDNA
Host DNA
Nucleus
Treatment Goal:
SVR1
Proviral DNA
Host DNA
Nucleus
Treatment Goal:
Life-long viral suppression1
Host DNA
Nucleus
Treatment Goal:
Life-long viral suppression1
 Majority of patients who achieve an SVR do not experience viral recurrence2
cccDNA=covalently closed circular DNA; HBV=hepatitis B virus.
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.
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ETR†
HCV RNA (log10 IU/mL)
Null Response
Partial Response
Relapse
Undetectable
RVR
EVR
SVR
Weeks After Start of Therapy
†Shown for 48-week fixed-treatment course; follow stopping rules for treatment.
Adapted from Ghany MG, et al. Hepatology. 2009;49:1335-1374.
34


SVR = HCV RNA negative (by a sensitive assay, <25 IU/mL) at
12 weeks after cessation of treatment1
99% of patients who achieved an SVR had undetectable
levels of HCV RNA in serum samples throughout the followup period2,*
› “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 12month intervals for the development of HCC1
*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.
35
530 patients followed for a median of 8.4 years
SVR patients
Non-SVR patients
29.9
30
27.4
26.0
10-year cumulative
occurrence rate (%)
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
25
21.8
20
15
10
8.9
5.1
5
0
All-cause
mortality
Van der Meer A, et al. JAMA 2012; 308:2584‒2593.
2.1
1.9
Liver-related
mortality or
liver transplant
HCC
Liver failure
36
Genotype 2
Genotype 3
(n=12,166)
(n=2904)
(n=1794)
SVR rate: 35%
0.3
Cumulative Mortality (%)
Genotype 1
SVR rate: 72%
0.3
0.3
0.25
0.25
0.25
0.2
NonSVR
0.15
0.15
0.15
P<.0001
P<.0001
P<.0001
0.1
0.1
0.1
0.05
0.05
0.05
SVR
0
1
2
NonSVR
0.2
0.2
Non-SVR
0
SVR rate: 62%
3
Years
4
5
SVR
6
0
0
1
2
3
4
SVR
5
6
0
0
Years
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.
1
2
3
Years
37
4
5
6
General:18 studies
n=29,269
Avg. FU=4.6 years
Cirrhotic: 9 studies
n=2,734
Avg. FU=6.6 years
HIV/HCV: 5 studies
n=2,560
Avg. FU=5.1 years
20
% patients after 5 years
18
16
14
12
11.3%
10.5%
10.0%
10
8
6
4.5%
4
3.6%
1.3%
2
0
General
Cirrhotic
SVR
Saleem J et al, AASLD 2014; Abstract #44
Co-infected
No SVR
38
General:21 studies
n=12,496
Avg. FU=6.1 years
Cirrhotic: 18 studies
n=4,987
Avg. FU=6.6 years
HIV/HCV: 3 studies
n=2,085
Avg. FU=4.7 years
20
% patients after 5 years
18
16
13.9%
14
12
10.0%
9.3%
10
8
5.3%
6
4
2.9%
2
0.9%
0
General
Cirrhotic
SVR
Saleem J et al, AASLD 2014; Abstract #44
Co-infected
No SVR
39
General: 1 studies
n=108
Avg. FU=4.2 years
Cirrhotic: 2 studies
n=1,046
Avg. FU=7.7 years
HIV/HCV: 2 studies
n=2,039
Avg. FU=4.9 years
20
% patients after 5 years
18
16
14
12
10
7.3%
8
6
4
2.7%
2.2%
2
0%
0.6%
0.2%
0
General
Cirrhotic
SVR
Saleem J et al, AASLD 2014; Abstract #44
Co-infected
No SVR
40
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
Mean Difference
Mean difference in scores (SVR versus treatment failure)
*
*
†
†
†
†
†
†
*
Bodily
Pain
General
Physical
Health Functioning
Role
Physical
Role
Social
Emotional Functioning
Vitality
Mental
Health
PCS
≠
MCS
SF-36 Scales
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.
41
Mean Change From Baseline
HRQOL Scale
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.
42
Mean per-patient-per-month (PPPM) follow-up costs
by treatment history and liver disease severity (2010)
HCV-related costs
Medical costs
Total costs
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.
43
The Good News
100
PegIFN
80
2017
2011
90+
2001
RBV
Standard
IFN
DAAs
70+
1998
55
60
1991
42
40
34
39
16
20
6
0
IFN
6 mos
IFN
12 mos
IFN/RBV
6 mos
IFN/RBV
12 mos
PegIFN
12 mos
PegIFN/
RBV
12 mos
PegIFN/
RBV/
DAA
DAA
+/- RBV
Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting,
April 27-28, 2011, Silver Spring, MD.
44
5’ UTR
region
3’ UTR
region
9.6 kb RNA
Polyprotein
C
E1
E2
p7 NS2
4A
NS3
NS4B
NS5B
NS5A
Polyprotein Processing
C
Core
E2
E1
Envelope
Glycoproteins
p7
NS2
Protease
NS3
NS4B
Helicase Serine
Serine
Protease
Protease
Cofactor
Simeprevir
Paritaprevir
Grazoprevir
Asunaprevir
*agents in red will be briefly
discussed but are
investigational in the US
NS4A
NS3-4A
protease
inhibitors
NS5A
Ledipasvir
Ombitasvir
Daclatasvir
Elbasvir
NS5B
RNA-dependent
RNA polymerase
NS5B
polymerase
inhibitors
nucleoside analogs
Sofosbuvir
Adapted from McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:1700-12
non- nucleoside analogs
Dasabuvir
Beclabuvir
45
NS3/4A
Protease
Inhibitors
Approved
Simeprevir
Boceprevir
Telaprevir
Paritaprevir/r
Grazoprevir
Phase 3
Asunaprevir
ABT-493
GS-9857
Phase 2
Vedroprevir
Sovaprevir
Not all inclusive.
Nucleotide
NS5B
Polymerase
Inhibitors
Non-Nucleoside
NS5B
Polymerase
Inhibitors
NS5A
Replication
Complex
Inhibitors
Sofosbuvir
Dasabuvir
Ledipasvir
Ombitasvir
Daclatasvir
Elbasvir
Beclabuvir
Velpatasvir
ABT-530
TMC647055
Odalasvir
MK-8408
PPI-668
ACH-3422
MK-3682
ALS-335
Cyclophilin
Inhibitors
SCY-635
46
Duration of Therapy (weeks)
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
NR
12
12
(no RBV)
(no RBV)
(with 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
*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.
47
Treatment-Naïve, No Cirrhosis
Percent (n/N)
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.
48
Treatment-Naïve, Compensated Cirrhosis
Percent (n/N)
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.
49
Duration of Therapy (weeks)
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
*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.
50
Duration of Therapy (weeks)
Sofosbuvir (400 mg qd) + PR
Eligible to receive pegIFN
Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd)
+ RBV
No
Cirrhosis
Compensated
Cirrhosis
12
12
12
24
(no RBV)
(+ RBV)
*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.
51
Treatment-Naïve, No Cirrhosis
Percent (n/N)
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 weeks
97 (73/75)
3 (2/75)
0 (0/75)
Treatment-Naïve, Compensated Cirrhosis
Daclatasvir + sofosbuvir
24 weeks (+RBV)
85 (155/183)
7* (16/219)
<1*‡ (3/468)
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.
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.
52
Duration of Therapy (weeks)
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
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February 24, 2016.
53
Treatment-Naïve, Treatment-Experienced
SVR12
Rate
Percent (n/N)
Relapse
Discontinuations
Rate
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.
54
Duration of Therapy (weeks)
Ledipasvir/sofosbuvir (90/400 mg qd)
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February 24, 2016.
No
Cirrhosis
Compensated
Cirrhosis
12
12
55
Genotype 5: Treatment-Naïve, Treatment-Experienced
SVR12
Rate
Ledipasvir/sofosbuvir 12 weeks
No cirrhosis
Compensated cirrhosis
97 (31/32)
89 (8/9)
Percent (n/N)
Relapse
Discontinuations
Rate
Due to Adverse Events
3 (1/32)
11 (1/9)
0 (0/32)
0 (0/9)
Genotype 6: Treatment-Naïve, Treatment-Experienced
Ledipasvir/sofosbuvir 12 weeks
No cirrhosis/compensated cirrhosis
96 (24/25)
4 (1/25)
0 (0/25)
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.
56
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]).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February 24, 2016.
57
Duration of Therapy (weeks)
Genotype 1a
No
Cirrhosis
Ledipasvir/sofosbuvir (90/400 mg qd) + RBV
With
Cirrhosis*
Genotype 1b
No
Cirrhosis
With
Cirrhosis*
12
12
12
12
(no RBV)
(with RBV)
(no RBV)
(with RBV)
24
24
(no RBV)
(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
NR
12
12
(no RBV)
(no RBV)
(with 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
*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.
58
Prior PR Failure, No Cirrhosis
Percent (n/N)
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)*
96 (286/297)
100 (91/91)
2 (7/293)
0 (0/91)
1 (3/297)
0 (0/91)
Simeprevir + sofosbuvir
12 weeks
95 (38/40)
3 (4/154)
0 (0/155)
Daclatasvir + sofosbuvir
12 weeks
100† (20/20)
--
--
Ombitasvir/paritaprevir/r + dasabuvir
Genotype 1a (with RBV), 12 weeks
Genotype 1b (no RBV), 12 weeks
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.
59
Prior PR Failure, Compensated Cirrhosis
Percent (n/N)
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.
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.
60
Duration of Therapy (weeks)
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
*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.
61
Duration of Therapy (weeks)
Sofosbuvir (400 mg qd) + PR
Eligible to receive pegIFN
Daclatasvir (60 mg qd)* + sofosbuvir (400 mg qd)
+ RBV
No
Cirrhosis
Compensated
Cirrhosis
12
12
12 (no RBV)
24 (+ RBV)
(IFN ineligible)
*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.
62
Prior PR Failure, Non-Cirrhotic
Percent (n/N)
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 weeks
94 (32/33)
3 (2/75)
0 (0/75)
Prior PR Failure, Compensated Cirrhosis
Sofosbuvir + PR
12 weeks
Daclatasvir + sofosbuvir
24 weeks (+RBV)
86 (30/35)
5* (9/181)
1† (1/103)
85‡ (155/183)
7* (16/219)
<1*§ (3/468)
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.
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.
63
Duration of Therapy (weeks)
Ledipasvir/sofosbuvir (90/400 mg qd) + RBV
Elbasvir/grazoprevir (50/100 mg) + RBV
Prior PR relapse
Prior PR failure
Ombitasvir/paritaprevir/r (25/150/100 mg qd) + RBV
No
Cirrhosis
Compensated
Cirrhosis
12
12 (with RBV)
24 (no RBV)
12 (no RBV)
16 (with RBV)
12 (no RBV)
16 (with RBV)
12
12
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.
64
Treatment-Naïve, Treatment-Experienced
Percent (n/N)
Ledipasvir/sofosbuvir 12 weeks
No cirrhosis
Compensated cirrhosis
Elbasvir/grazoprevir*
Prior PR relapse, 12 weeks (no RBV)
Prior PR failure, 16 weeks (with RBV)
Ombitasvir/paritaprevir/r + RBV
12 weeks
No cirrhosis
Compensated cirrhosis
SVR12
Rate
Relapse
Rate
Discontinuations
Due to Adverse Events
93 (39/42)
100 (10/10)
7 (3/42)
0 (0/10)
0 (0/42)
0 (0/10)
100 (2/2)
100 (5/5)
0 (0/2)
0 (0/5)
0 (0/2)
0 (0/5)
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.
65
Duration of Therapy (weeks)
Ledipasvir/sofosbuvir (90/400 mg qd)
No
Cirrhosis
Compensated
Cirrhosis
12
12
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.
66
Genotype 5: Treatment-Naïve, Treatment-Experienced
Percent (n/N)
Ledipasvir/sofosbuvir 12 weeks
No cirrhosis
Compensated cirrhosis
SVR12
Rate
Relapse
Rate
Discontinuations
Due to Adverse Events
97 (31/32)
89 (8/9)
3 (1/32)
11 (1/9)
0 (0/32)
0 (0/9)
Genotype 6: Treatment-Naïve, Treatment-Experienced
Ledipasvir/sofosbuvir 12 weeks
No cirrhosis/compensated cirrhosis
96 (24/25)
4 (1/25)
0 (0/25)
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.
67
Genotype
No 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
5 and 6
Compensated Cirrhosis
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)
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]).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February 24, 2016.
68
Duration of Therapy (weeks)
Ledipasvir/sofosbuvir (90/400 mg qd) + 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
Daclatasvir (60 mg qd)‡ + sofosbuvir (400 mg qd)
No Cirrhosis
Compensated Cirrhosis
12
12 (with RBV)
24 (no RBV)
12
12
12
16
12
16
12
24 (+ RBV)
*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.
69
Duration of Therapy (weeks)
Ledipasvir/sofosbuvir (90/400 mg qd) + RBV
No Cirrhosis
Compensated Cirrhosis
12
24
Weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]).
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. February 24, 2016.
70
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
*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.
71

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.
72

Prospective, observational cohorts
›
Registry Characteristics
SVR Registry: SVR12 achievers
(n=5433)
SVR
(n=5433)
54
Sequence
(n=563)
54
Male (%)
63
78
White (%)
85
84
Cirrhotics (%)
20
22
HCV genotype (%)
1
2
3
4
5
6
67
10
20
3
<1
<1
62
5
32
<1
<1
0
 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.
Median age
(years)
73
SVR12
SVR12
SVR12
(baseline F0/F1)
(baseline F2/F3)
(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 RNA
PWID, MSM
Alcohol, Obesity, Diabetes
No
HCV RNA
Every 12 Months
Non-Invasive Tests
Every 12 Months
Serfaty L, et al. Liver Int. 2016;36(suppl S1):67-71.
Yes
Lifestyle Changes
Diabetes Control
Liver Biopsy if
Elevated ALT/AST
Liver Ultrasound
Every 6 Months
74
Strategies To Advance HCV Patient Care
PATIENT
IDENTIFICATION
Outreach & Awareness Need For:
• Patient Awareness
regarding risk factors &
testing
• Provider education &
awareness regarding
HCV testing
DiagnosisNeed For:
• HCV Testing Protocols
• Clearly defined roles &
responsibilities for HCV
testing among providers
• Patient education &
engagement upon
diagnosis
HCV DISEASE
MANAGEMENT
SPECIALIST
REFERRAL
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 PatientsNeed For:
75
• HCV care management
protocols/AASLD Guidelines
• Clearly defined roles &
responsibilities for HCV management
• Patient involvement to improve
adherence & treatment success
75
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 rates

76
PCP HCV Screening, Referral & Treatment
Primary Care Visit
Birth Age Cohort – 1945-65
Risk Factors
Abnormal LFT
HCV antibody OraQuick or
Phlebotomy
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 (needlesticks, mucosal exposures)
HIV-infected persons
Birth to an infected mother
POSITIVE
HCV RNA PCR Quantitative
NEGATIVE
REFER TO
GI/HEPATOLOGY
HCV Genotype
Hepatitis B Surface antigen
Hepatitis B Surface Antibody
No Referral
PRIMARY CARE
PROVIDER
TREATMENT PER
HCV PROTOCOL
Hepatitis B Core Total Antibody
Hepatitis A Total Antibody
HIV Antibody
Abdominal Ultrasound & Fibroscan
Hepatitis A & B Vaccination
Alcohol Abstinence Counselling
Retrospective analysis (2012-2015)
›
Academic/speciality sites (n=6)
›
Multiple ECHO sites (PCP and
subspecialist)
›

Demographics of patients are similar,
except for race and treatment history
›

More treatment-experienced,
genotype 1 and 3 patients were
treated by specialist
Regimens
›

Arizona, New Mexico, Oklahoma,
Texas, Utah, Washington
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
SVR12 Rates (mITT)
ECHO
100
Specialty
98%
97%
93%
89%
81%
80
SVR12 (%)

82%
60
40
20
0
1
(n=150|373)
3
(n=43|67)
2
(n=48|82)
Genotype
Georgie F, et al. J Hepatol. 2016;64(suppl 2):S818-S819.
Abstract SAT-260.
78
Multicenter, open-label, phase 4
study (n=600 HCV patients)
›
Washington, DC (3 community health)
›
Providers underwent 3-hour training on
AASLD-IDSA guidelines
›


100
Ledipasvir/sofosbuvir per full
prescribing information
94%
97%
95%
92%
80
Patients
›
Male (66%), HCV genotype 1a (72%),
F3/4 (36%), HIV coinfection (24%)
›
HCV treatment experienced (18%),
HCV RNA >6 million (19%)
60
40
Treatment duration
›

SVR12 Rates
SVR12 (%)

8 (5%), 12 (90%), 24 (5%) weeks
HCV treatment administered
independently by PCPs and NPs was
safe and equally effective as with
experienced specialists
20
0
Overall
PCP
NP
Specialist
(n=304)
(n=60)
(n=79)
(n=165)
Specialist: infectious disease or hepatology.
Kattakuzhy S, et al. J Hepatol. 2016;64(suppl 2):S224. Abstract LBP524.
79
Pangenotypic
“breakthrough”
sofosbuvir/velpatasvir
(Gilead) – expected
June 2016
ABT-493(NS3/4A) + ABT530 (NS5A) (AbbVie) –
expected late 2017
Hep B
NASH
tenofovir alafenamide
(Gilead)
obeticholic acid
(Phase III, Intercept)
Liver
Cancer
nivolumab
(Opdivo®, BMS)
Therapeutic
Vaccines – in
Phase I and II
clinical trials
(Gilead, ABIVAX,
Inovio,
Ichor/Jansen)
elafibranor
(Phase III, Genfit)
sorafenib
Many others
(Nexavar®, Bayer FDA approved Oct
2015)
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.htm
www.cancerresearch.org
80