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Transcript PPT - IAS-USA
The Top 5 Things to Remember about
Treating HCV
Susanna Naggie, MD, MHS
Associate Professor of Medicine
Duke University School of Medicine
Durham, North Carolina
FORMATTED: MM/DD/YY
New York: New York: March 23, 2016
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
Learning Objectives
After attending this presentation, participants will be able to:
List the options for assessing liver fibrosis
Describe the AASLD/IDSA Guideline recommendations
for management and treatment of HCV Infection
Describe the drug interactions with antiretrovirals and
HCV direct acting antivirals (DAAs)
Describe treatment plans for difficult to treat patients,
including those with cirrhosis and NS5A drug resistanceassociated viral variants
Slide 2 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
Grazoprevir is a…
20%
3/
4A
Pr
ot
ea
se
In
hi
bi
to
No
NS
r
5A
nnu
In
cle
hi
NS
bi
os
5B
to
id
Nu
r
e
po
cle
ly
ot
m
A
i
d
er
tro
ep
a.
pi
.
ol
ca
y
m
lp
er
la
as
ce
e
Iw
i..
.
ou
ld
lik
e
to
v.
..
13% 12%11%
NS
5B
NS
1. NS3/4A Protease Inhibitor
2. NS5A Inhibitor
3. NS5B Non-nucleoside
polymerase inhibitor
4. NS5B Nucleotide
polymerase inhibitor
5. A tropical place I would like
to visit one day
44%
Slide 3 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
Enter Question Text
80%
The AASLD/IDSA–Guidelines are:
1. Funded by industry
2. Updated frequently as new data
sin
ce
th
in
g
Th
e
br
ea
d
sli
ce
d
ist
s
ep
at
ol
og
gu
i..
.
fo
rH
he
se
A
re
so
ur
ce
of
t
as
ne
w
er
he
ar
d
nt
ly
ne
v
av
e
Ih
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
10%
3% 3%
da
t..
.
in
du
st
ry
by
fre
qu
e
Fu
nd
ed
Up
da
te
d
Slide 4 of 34
4%
be
st
are released
3. I have never heard of these
guidelines
4. A resource for Hepatologists
5. The best thing since sliced bread
When and In Whom to
Initiate HCV Therapy
Slide 5 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
www.hcvguidelines.org
All of the non-invasive markers below are
suggestive of cirrhosis except:
42%
1. APRI 2.1
2. FibroSure 0.85
3. Transient elastography 7.5
Fib
ns
ie
Tr
a
Slide 6 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
18%
7%
ro
nt
Su
el
re
as
0.
to
85
gr
ap
hy
7.
Th
5
is
kP
is
a
at
ric
FI
k
Bqu
4
es
3.
tio
8
n
as
th
ey
...
10%
AP
RI
2.
1
kPa
4. FIB-4 3.8
5. This is a trick question as they
are all associated with
cirrhosis
22%
Staging of Liver Disease:
Liver Biopsy
• Gold standard
• Invasive
- Morbidity (3/1,000)
- Mortality (1/10,000)
• Observer variability
• Sampling error
• Costly
F1
Slide 7 of 34
F2
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
F3
F4
Rockey DC, et al. Hepatology. 2009;49:1017-1044.
Regev A, et al. Am J Gastroenterol. 2002:2614-2618.
Alternatives to Liver Biopsy
►Noninvasive approaches
– Serum markers
• Standard laboratory tests: APRI (<0.3,>2), FIB-4 (>3.25)
• Commercial assays (FibroSure) (>0.8)
– Radiographic tests
• Elastography
►Limitations
– Ability to distinguish F1 versus F2, etc.
• Better to differentiate advanced versus early fibrosis
– Serologies impacted by inflammation
– Indeterminate outcomes common
Slide 8 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
Lin ZH, et al Hepatology. 2011;53:726-736.
Vallet-Pichard A, et al. Hepatology. 2007;46:32-36.
Myers RP, et al. Dig Dis Sci. 2003;48;146-153.
Friedrich-Rust M, et al. Z Gastroenterol. 2013 Jan;51:43-54.
Radiographic Assessments
Newer Methods
► Ultrasound, CT, MRI
– Conventional studies are unhelpful in assessment of fibrosis
unless patient has decompensated cirrhosis
► Elastography
► Transient elastography
– Methodology
• Ultrasonic transducer sends a vibration wave into the liver
• Elastic shear wave propagates through the liver
• Velocity of wave correlates with tissue stiffness
– Test characteristics
• Mean AUROC for the diagnosis of:
– Severe fibrosis: 0.89 (95% CI, 0.88-0.91)
– Cirrhosis: 0.94 (95% CI, 0.93-0.95)
Slide 9 of 34
Friedrich-Rust M, et al. Z Gastroenterol. 2013 Jan;51:43-54.
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
HIV/HCV Co-infection
Slide 10 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
www.hcvguidelines.org.
Hepatitis C Virus
HCV Genome
5 UTR
region
9.6 kb RNA
IRES-mediated translation
Polyprotein
C
3 UTR
region
E1
E2
NS2
NS3
A
NS4B
A
NS5
B
Polyprotein Processing
C
Core
E1
E2
Envelope
glycoproteins
p7
NS2
NS3
4A
NS4B
Serine
Protease
Serine
Protease
Cofactor
NS3-4A
Protease
Inhibitors
Slide 11 of 34
NS5A
Inhibitors
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
NS5A
NS5B
RNA
dependent
RNA
polymerase
NS5B
Polymerase
Inhibitors
Adapted from Naggie et al. J Antimicrob Chemother 2010
Agents and
Regimens
Antiviral
Regimen
NS3
Paritaprevir/r/ombitasvir FDC
+ dasabuvir (PrO+D)
Simeprevir + sofosbuvir
RBV
1a only
Sofosbuvir + ribavirin
Slide 12 of 34
Nuc
NS5B
Ledipasvir/sofosbuvir FDC
Velpatasvir/sofosbuvir* FDC
Non-Nuc
NS5B
Daclatasvir + sofosbuvir
Elbasvir/grazoprevir FDC
NS5A
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
*pending FDA approval
The current recommended length of therapy
for a treatment experienced GT-1 infected
patient without cirrhosis is:
1. 6 weeks
83%
2. 8 weeks
3. 12 weeks
4. 16 weeks
5. 24 weeks
8%
1%
6
Slide 13 of 34
ks
ee
w
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
8
ks
ee
w
7%
1%
12
ks
ee
w
16
ks
ee
w
24
ks
ee
w
Recommended regimens for treatment-naïve and
experienced patients with HIV/HCV genotype 1
without cirrhosis
Regimen
Weeks
Rating
Daclatasvir + sofosbuvir*
12
I, A
Elbasvir/grazoprevir (except GT1a with NS5A RAV)*
12
I, A
Ledipasvir/sofosbuvir**
12
I, A
Paritaprevir/r/ombitasvir + dasabuvir + ribavirin , GT 1a
12
I, A
Paritaprevir/r/ombitasvir + dasabuvir, GT 1b
12
I, A
Simeprevir + sofosbuvir
12
I, A
*recommended in first wave PI failures (ELB/GRZ requires RBV)
**recommended in first wave PI failures and prior SOF failure (add RBV)
Slide 14 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
www.hcvguidelines.org.
Take Home #1: Cure is same for HIV/HCV
100
*
97 100
95 95
96 97
96
*
92
90
92
89
80
70
60
50
40
30
20
10
0
DAC/SOF
ELB/GRZ
LDV/SOF
HIV/HCV
Slide 15 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
HCV
PrOD
GECCO
Naggie et al, NEJM 2015; Sulkowski et al, JAMA 2015; Wyles et al,
NEJM 2015; Rockstroh et al, Lancet HIV 2015; Christensen et al,
CROI 2016; Sulkowski et al, NEJM 2015
Simeprevir
Sofosbuvir
Ledipasvir
Daclatasvir
P/r/O + D
Drug
Interaction
Substrate of
CYP3A4,
OATP1B1/3
Substrate of
P-gp and BCRP
Inhibitor/
Substrate of P-gp
and BCRP
Inhibitor of
OATP1B1/3, BCRP,
Substrate of P-gp
and CYP3A4
Inhibit/Sub of
UGT1A1,OATP1B1/3,
BCRP, CYP3A4,
CYP2C8, P-gp
ATV/r
No data
No data
LDV ↑; ATV ↑
DCV ↑*
ATV ↑; PAR ↑
DRV/r
SIM ↑; DRV ↔
SOF ↑; DRV ↔
LDV ↑; DRV ↔
ALLY-2 ↔
DRV ↓; PAR ↓
LPV/r
No data
No data
No data
ALLY-2 ↔
LPV ↔; PAR ↑
TPV/r
No data
No data
No data
No data
No data
EFV
SIM ↓; EFV ↔
SOF ↔; EFV ↔
ION-4 ↔
DCV ↓*
No PK data**
RPV
SIM ↔; RPV ↔
SOF ↔; RPV ↔
LDV ↔; RPV ↔
ALLY-2 ↔
PAR ↑; RPV ↑
ETV
No data
No data
No data
No data*
No data
RAL
SIM ↔; RAL ↔
SOF ↔; RAL ↔
LDV ↔; RAL ↔
ALLY-2 ↔
PrOD ↔; ↑ RAL
ELV/cobi
No data
Cobi ↑; SOF ↑
LDV ↑; SOF ↑
No data
No data
DLG
No data
No data
LDV ↔; DLG ↔
ALLY-2 ↔
PAR ↓; DLG ↑
MVC
No data
No data
No data
No data
No data
TDF
SIM ↔; TFV ↔
SOF ↔; TFV ↔
LDV ↔; ↑TFV
DCV ↔; TFV ↔
PrOD ↔; TFV ↔
* Decrease DCV dose to 30mg QD, Increase DCV dose to 90mg QD, ** PrOD + EFV led to premature study discontinuation due to toxicities
Slide 16 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
Slide courtesy of Jennifer Kiser
ARV Interaction Score Card 2015
Ledipasvir and TDF
LDV/SOF +
AUCtau (ng.h/mL)
Slide 17 of 34
EFV/TDF/FTC
RPV/TDF/FTC
RAL +
TDF/FTC
3600 (4400)
4286 (4780)
4010
ATV/r +
TDF/FTC
DRV/r +
TDF/FTC
5460/5740
5490/4260
German et al, Clin Pharm 2014; German et al. CROI 2015 Abstract 82; Naggie et al. NEJM 2015
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
Real World Data suggests higher relapse to
LDV/SOF with PPI
►PPI use in TARGET 28%
Slide 18 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
Terrault et al, AASLD 2015
A Clinical Caveat: LDV and Acid Suppressing
Medications
►Healthy volunteer data only
– Dosing recommendations is difficult for patients
►Possible relevance in HIV in particular?
Slide 19 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
German et al, AASLD 2015
ARV Interaction Score Card 2016
Slide 20 of 34
Velpatasvir/
Sofosbuvir
Ledipasvir/
Sofosbuvir
Drug
Interactions
Substrate of CYP3A4, Pgp, OATP1B1/3;
Inhibitor of BCRP, P-gp,
CYP2C8, 3A4, UGT1A1
Substrate of
P-gp, BCRP, OATP, CYP2B6,
2C8, 3A4; Inhibitor of Pgp, BCRP, OATP
Inhibitor/
Substrate of P-gp
and BCRP
Inhibit/Sub of
UGT1A1,OATP1B1/3,
BCRP, CYP3A4,
CYP2C8, P-gp
ATV/r
GRZ & ELB ↑, ATV ↑
VEL ↑; ATV ↑
LDV ↑; ATV ↑
ATV ↑; PAR ↑
DRV/r
GRZ & ELB ↑; DRV ↔
VEL ↑; DRV ↔
LDV ↑; DRV ↔
DRV ↓; PAR ↓
LPV/r
GRZ & ELB ↑; DRV ↔
VEL ↑; LPV ↑
No data
LPV ↔; PAR ↑
TPV/r
No data
No data
No data
No data
EFV
GRZ & ELB↓, EFV ↓
VEL ↓; EFV ↔
ION-4 ↔
No PK data**
RPV
GRZ & ELB ↔; RPV ↔
VEL ↔; RPV ↔
LDV ↔; RPV ↔
PAR ↑; RPV ↑
ETV
No data
No data
No data
No data
RAL
GRZ & ELB ↔; RAL ↑
VEL ↔; RAL ↔
LDV ↔; RAL ↔
PrOD ↔; ↑ RAL
ELV/cobi
No data
VEL ↑; SOF ↑
LDV ↑; SOF ↑
No data
DLG
GRZ & ELB ↔; DLG ↑
VEL ↔; DLG ↔
LDV ↔; DLG ↔
PAR ↓; DLG ↑
MVC
No data
No data
No data
No data
TDF
GRZ & ELB ↔; TFV ↑
VEL ↔; TFV ↑
LDV ↔; ↑TFV
PrOD ↔; TFV ↔
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
P/r/O + D
Slide courtesy of Jennifer Kiser
Elbasvir/
Grazoprevir
Take Home #2: Shortening therapy with
current DAA increases relapse
HCV MONO
Tx Naïve, No cirrhosis:
ION-3
100
94
93
HIV/HCV COINFECTION
Naïve : ALLY-2 (DCV/SOF)
95
100
90
80
50
40
HCV RNA <6 million IU/mL
-8 weeks 121/123 (98%)
-12 weeks 129/131 (98%)
SVR12, %
SVR %
60
96.4
75.6
80
70
Tx
60
40
30
20
20
10
0
Slide 21 of 34
-RBV
+RBV
8 weeks
20 relapse (4.5%)
-RBV
12 weeks
3 relapse (1%)
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
80/83
0
31/41
12 weeks
8 weeks
1 relapse (1%) 10 relapse (25%)
ION-3 Kowdley et al. NEJM; Wyles et al. CROI 2015 LB151
Shortening therapy increases impact of
baseline predictors
PRO
►Baseline viral load can predict decrease
risk of relapse
►Real World Cohorts
– TRIO – 242/254 (95%)
CON
►Baseline viral load is not the
only predictor and has poor
accuracy
►Real World Cohorts
– VA – greater failure for 8 weeks
in black veterans
– TARGET – 150/154 (97%)
– GECCO – 175/191 (92%)
– Only ~40% of TARGET eligible
got 8 weeks – under use? Good
medical decision making?
• 24/26 HIV/HCV (92%)
►Cheaper
►Failure = resistance 65%
Terrault et al, AASLD 2015; Curry et al, AASLD 2015; Backus et al. AASLD 2015
Slide 22 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
Shortening therapy increases
impact of baseline predictors
Slide 23 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
O’brien et al, OFID 2015
Gender and Race in Real World Experience
Gender
►TARGET (43% overall)
Race
►TARGET – no signal (20%)
– Women more likely to get 8 weeks (54% vs
41%)
►TRIO – trend to lower SVR (18%)
– Women higher SVR (OR 2.0)
►TRIO (47% overall)
– Also more likely to get 8 weeks (54% vs
44%)
– SVR same
►VA – lower SVR – lost when
analysis only of 12 week
duration (38% black)
Terrault et al, AASLD 2015; Curry et al, AASLD 2015; Backus et al. AASLD 2015
Slide 24 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
Recommended regimens for HIV/HCV
genotype 1 and compensated cirrhosis
Regimen
Weeks
Rating
Elbasvir/grazoprevir (except GT1a with NS5A RAV)*
12
I, A
Paritaprevir/r/ombitasvir + dasabuvir, GT 1b
12
I, A
12
I, A
Daclatasvir + sofosbuvir ± ribavirin (only PI failures)
24
IIa, B
Ledipasvir + sofosbuvir + ribavirin*
12
I, A
Ledipasvir + sofosbuvir**
24
*recommended in first wave PI failures (ELB/GRZ requires RBV)
**recommended in first wave PI failures and prior SOF failure (add RBV)
I, A
Treatment Naïve or Experienced
Treatment Naïve Only
Ledipasvir + sofosbuvir
Treatment Experienced Only
Slide 25 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
www.hcvguidelines.org
Take home #3: Cirrhosis requires
RBV or longer therapy for some …but not all
SIRIUS: LDV/SOF+RBV X 12W or
LDV/SOF X 24W in TE Cirrhosis
100
90
80
70
60
50
40
30
20
10
0
90
96
97
100
100
SVR12
100
100
100
80
60
40
74/77
75/77
LDV/SOF LDV/SOF/RBV LDV/SOF
12 Weeks*
12 Weeks
24 Weeks
*not arm in SIRIUS – shown for historic comparison
Slide 26 of 34
TURQUOISE-II: P/r/O/D X12 weeks in
Genotype 1b Cirrhosis
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
20
0
60/60 60/60
60/60
60/60
RVR
SVR4
SVR12
EOT
Poordad et al. EASL 2015; Bourliere et al. Lancet ID 2015;
Reddy et al. Hepatology 2015.
Take Home #4: NS5A RAVs matter
1a
Fold-change
1b
M28T
Q30R
L31M/V
Y93H/N
LDV
20x
>100x
>100x/
>100x
>1,000x/
>10,000
Ombitasvir
>1000x
>100x
<3x
>100x
>10,000x/
>10,000x
<10x
20x/50x
DCV
>100x
>1000x
>100x/
>1000x
>1,000x/
>10,000x
<10x
20x/50x
Elbasvir
20x
>100x
>10x
>1,000x/
>1,000x
<10x
>100x/--
Velpatasvir
<10x
<3x
20x/50x
>100x/
>1000x
<3x/--
ACH-3102
30x
20x
<10x
>100x/>100x
<3x/<3x
ABT-530
<3x
<3x
<3x
<10x/<10x
<3x
<3x/<3x
MK-8408
<10x
<10x
<10x
<10x
<10x
<10x
>100x
L31V
Y93H/N
>100x/--
Wang C. AAC 2012. Cheng G. #1172. EASL 2012. Zhao Y. #A845 EASL 2012. Yang G. EASL 2013. Ng T. #639 CROI 2014. Asante-Appiah E. AASLD 2014.
Slide 27 of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
What about NS5A Baseline
Resistance?
ALLY-3: Daclatasvir + sofosbuvir X 12 weeks
in GT3 infection
100
90
80
70
60
50
40
30
20
10
0
C-EDGE: Grazoprevir/elbasvir X 12 weeks in
TN GT1 infection
RAV at BL SVR12 All SVR12
RAV
<5X
SVR12
100 100
GT1a
67
20
Without Cirrhosis
M28V
SVR12
RAV
>5X
A30
25
With Cirrhosis
Y93H
BL
RAV
12%
19/154
58%
11/19
90%
9/10
22%
2/9
No
RAV
88%
135/154
99%
133/135
--
--
BL
RAV
14%
18/130
94%
17/18
100%
1/1
94%
16/17
No
RAV
86%
112/130
100%
112/112
--
--
GT1b
Nelson et al. Hepatology 2015; Zeuzem et al. Ann Int Med 2015
Slide 28 of 34 From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
Baseline NS5A resistance and
LDV/SOF
<100X
>100X
No RAVs
Slide 29 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
Sarrazin C. #1926 AASLD 2014.
Recommended regimens for HCV genotype
2&3 with or without CP-A cirrhosis
Regimen GT2
Weeks
Rating
Treatment naïve or Treatment experienced
PEG/RBV without cirrhosis
Daclatasvir + sofosbuvir
12
IIa, B
Sofosbuvir + RBV
12
I, A
Treatment experienced SOF/RBV and/or cirrhosis
Daclatasvir + sofosbuvir +
ribavirin
16-24
IIa, B
Sofosbuvir + RBV*
16-24
IIa, B
12
IIa, B/C
Sofosbuvir + PEG/RBV**
Slide 30 of 34
Regimen GT3
Weeks
Rating
Treatment naïve or Treatment experienced
PEG/RBV without cirrhosis
Daclatasvir + sofosbuvir
12
I, A
Sofosbuvir + PEG/RBV
12
I, A
Treatment experienced SOF/RBV* and/or
cirrhosis
Daclatasvir + sofosbuvir +
ribavirin
24
IIa, B
Sofosbuvir + PEG/RBV
12
I, A
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
Take Home #5: More to come for GT 2-6
Slide 31 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
Take Home
►#0.5 – staging of liver disease is required
►#1 – Cure is same for HIV/HCV
►#2 – Shortening therapy increases relapse and impact of
baseline predictors
►#3 – Cirrhosis requires RBV and/or extending therapy for most
but not all regimens
►#4 – NS5A RAVs matter for initial and re-treatment
►#5 – Pangenotypic is coming
Slide 32 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
The real challenge…
Slide 33 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
Questions
Slide 34 of 34
From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.