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
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NS
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5A
nnu
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hi
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bi
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ld
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e
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..
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
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From S Naggie, MD, at New York, NY: March 23, 2016, IAS-USA.
10%
3% 3%
da
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ry
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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.