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Current HCV Treatment by Genotype
Empire Liver Foundation
Ira M. Jacobson, MD Chairman, Department of Medicine
Mount Sinai Beth Israel
Professor of Medicine
Co-Director, Liver Institute
Icahn School of Medicine at Mount Sinai
New York, New York
Objectives
• To understand the prevalence of HCV and
distribution of HCV genotypes
• Describe the HCV lifecycle and how specific drugs
target the HCV polypeptide sequence
• Explain circumstances where it is important to test for
possible drug resistance
• Understand the landscape in regards to advances
made in the evolution of treating HCV over the past
20+ years
• Understand the HCV genotypes and the drug
regimens that work to eradicate HCV on each
genotype
• Approximately 3.5 million people in the United States are chronically
infected with HCV (1.3%)
– Including populations excluded from NHANES (e.g., the incarcerated,
homeless, institutionalized, and those living on Native American
reservations) brings the total estimate to 4.6 million2
• Seroprevalence is higher in
– 1945-1965 birth cohort (3.5%)
– Non-Hispanic blacks (2.2%)
– Males (1.9%) vs females (1.1%)
• Many diagnosed patients remain
untreated3
• Birth cohort screeing introduced
HCV: A Major Public Health Problem
NHANES=National Health and Nutrition Examination Survey. aNHANES data as of 2010; bNHANES data, 2001-2008.
1. Ditah I, et al. J Hepatol. 2014;60:691-698
2. Edlin BR, et al. Hepatology. 2015;62:1353-1363
3. Yehia BR, et al. PLoS ONE. 2014;9:1-7.
50% Undiagnosed
50% Diagnosed
Distribution of Hepatitis C Genotypes
Epidemiology of Infectious Diseases. Available at: http://ocw.jhsph.edu. Copyright © John Hopkins Bloomberg School of Public Health. Creative Commons BY-NC-SA.
HCV Polypeptide Sequence
T. Asselah.
The HCV Polymerase (NS5B)
The active site of the HCV polymerase is highly conserved…
Explains why sofosbuvir is the backbone of several regimens
What’s Special About the Active Site of the HCV Polymerase?
Feature Therapeutic Implication
Highly conserved across genotypes Pangenotypic efficacy of
potent inhibitors
Low replicative fitness conferred by
amino acid substitutions High resistance barrier
Resistance Considerations
• Most pts with failure of current DAAs have emergent resistance-
associated variants (RAVs), especially to the NS5A class
– NS5A RAVs persist much longer than PI RAVs
• 15% of pts have baseline NS5A RAVs with variable effects on
GT1a response
• Second-generation drugs are designed to cover RAVs
Which classes are
prone to resistance?
Protease, NS5A,
and nonnucleotide
NS5B inhibitors
Barrier to PI and
NS5A resistance
Higher for GT1b
vs GT1a
Where HCV Therapy Stands Now
• Interferon is gone in the U.S.; ribavirin…not quite
• SVR in over 95% of patients
• “Difficult to treat” populations no longer difficult
– African-Americans
– HIV coinfected
– Cirrhosis
– Older age
– Renal failure and transplant
– Liver transplant
– Persons who use IV drugs (PWID)
• Confidence that SVR12 = cure
• Cost and access issues persist, but improving
Rising Cure Rates for Chronic HCV (GT1)
16%
35%
44%
70-80%
80-90% >95%
0%
20%
40%
60%
80%
100%
1991 1998 2001 2011 2013 2014+
IFN
IFN/RBV
PegIFN/RBV
Telaprevir or Boceprevir + PegIFN/RBV
PR/SMV PR/SOF
IFN-Free DAA Combination
Regimens
Cu
re R
ate
*
Year
The Evolution of HCV Therapy
Curability of HCV
without IFN
Frequent curability of diverse
populations without IFN
Simeprevir, sofosbuvir with IFN (GT1)
2015 2011 2012 2013 2014
Telaprevir and
boceprevir
Daclatasvir: DCV+ASV
(Japan) DCV+SOF (Europe)
Ledipasvir +
sofosbuvir (GT1)
Paritaprevir/r-
ombitasvir/ dasabuvir
± RBV (GT1)
Simeprevir +
sofosbuvir (GT1)
First approved IFN-free therapy: sofosbuvir + RBV (GT2,3)
DCV + SOF (GT3)
(GT1 2016)
Interferon Era 2016
Grazoprevir+
Elbasvir
(GT1,4
1991-
Sofosbuvir +
velpatasvir
(all genotypes)
DAA: direct-acting antiviral; GT: genotype;
IFN: interferon; PI: protease inhibitor; NI: nucleoside/nucleotide inhibitor; RBV: ribavirin; r: ritonavir.
Structural domain Nonstructural domain
Approved Direct-Acting Antiviral Agents from Multiple Classes: Combination Regimens for HCV in 2016
3’UTR 5’UTR Core E1 E2 NS2 NS4B NS3 NS5A NS5B P
7
Ribavirin
Polymerase
Daclatasvir (DCV)
Ledipasvir (LDV)
Ombitasvir (OMV)
Elbasvir (EBV)
Velpatasvir
Sofosbuvir
(SOF)
Dasabuvir
(DSV)
NS5B
NUC
Inhibitors
NS5A
Replication
Complex
Inhibitors
NS5B
Non-NUC
Inhibitors (NNI)
Simeprevir (SMV)
Paritaprevir/ritonavir
(PTV/r)
Grazoprevir (GZR)
NS3
Protease
Inhibitors
Protease
4A
(RBV)
“previr” = protease inhibitor; “asvir” = NS5A inhibitor; “uvir ”= polymerase inhibitor Courtesy of Albert Min MD.
SVR and All-Cause Mortality in CHC
Patients with Advanced Fibrosis
530 patients with all genotypes followed for a median of 8.4 years
Baseline factors
significantly associated
with all-cause mortality:
– Older age
– Genotype 3 (2-fold
increase in mortality
and HCC)
– Higher Ishak
fibrosis score
– Diabetes
– Severe alcohol use
SVR patients Non-SVR patients
10
-Year
Cu
mu
lati
ve
Occu
rren
ce R
ate
(%
)
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
Van der Meer A, et al. JAMA. 2012; 308:2584‒2593.
Cirrhosis Regression and Fibrosis Reduction Following SVR (any genotype)
Fibrosis Reduction
• After treatment, the area of fibrosis decreased in 34/38 (89%) of patients
• Post-treatment liver biopsies showed a significantly reduced area of fibrosis, with a
median individual decrease of 71.8%
Sample Liver Biopsy
Pre-treatment (F4) Post-treatment (F3)
7
14 38
15
0%
20%
40%
60%
80%
100%
Pre-treatment Post-treatment
F1 F2 F3 F4
2
Cirrhosis Regression in 61% of Patients
Prospective study of patients with pre-treatment cirrhosis and an SVR with IFN-based therapy (enrolled in 2009-2010) to assess the
impact of SVR on the full spectrum of histopathologic features of HCV-related cirrhosis. N=38, median f/u 67 months (range, 54-110 months).
Adapted from D’Ambrosio R, et al. Hepatology. 2012;56:532-543.
Evolution of Portal Pressure After DAA Therapy
∆HVPG Absolute ∆: -2.63 ± 0.38 mmHg; p<0.001
Relative ∆: -23 ± 2.9%
0
6
10 12
16
20
30
HV
PG
(m
mH
g)
BL BL FU FU 13.1 ± 0.7 mmHg 10.4 ± 0.79 mmHg
Earlier portal hypertension is more
reversible than advanced PHT
Subclinical portal hypertension at BL
Resolved 63% No progression
HVPG 10–15 mmHg at BL Resolved 14% Regression 29% No progression
Pronounced portal hypertension at BL
No resolution Regression 5% Increase 20%
Mandorfer M, et al. EASL. 2016. Barcelona. #PS005.
Extra-hepatic Manifestations of
HCV Infection
Cacoub P, et al. Dig Liver Dis 2014; 46(Suppl 5):S165–S173; Negro F, et al. Gastroenterology 2015; 149:1345–1360; Englert Y, et al. Fertil Steril 2007; 88:607–11; Samuel DG & Rees IW. Frontline Gastroenterol 2013; 4:249–254.
Renal
impairment
Thyroid dysfunction
Peripheral neuropathy
Cardiovascular/
metabolic diseases
Mixed
cryoglobulinemia
Hematological disorders/
malignancies
Neuropsychiatric
manifestations
Type II
diabetes
Treatment of HCV Is Associated with Reduced
Risk for Type 2 Diabetes Mellitus
1.. Arase Y, et al. Hepatology 2009; 49:739–744; 2. Romero-Gomez M, et al. J Hepatol 2008; 47:721–727
Japanese retrospective study: 2842 patients treated with IFN ± RBV were
followed for a mean of 6.4 years1
SVR was associated with a
66% reduction in the development of T2DM
Spanish HCV chronic HCV cohort study:
1059 patients treated with IFN + RBV for
24/48 weeks2
SVR reduces the risk of IFG and/or T2DM
development
P=0.0003
Follow up (years)
50
30
20
10
0
40
0 10 20
Cu
mu
lati
ve d
evelo
pm
en
t
rate
of
T2D
M p<0.001
SVR
(n = 1175)
Non-SVR
(n = 1667)
Pati
en
ts w
ith
ou
t IF
G a
nd
/or
T2D
M
Follow-up (months)
SVR
NR Censored
Censored
0 24 48 72 96
1.0
0.8
0.6
0.4
0.2
0.0
Treatment of HCV Is Associated with Reduced
Risk for Cardiovascular Complications
• ACS, acute coronary syndrome. • Hsu YC, et al. Gut 2015; 64:495–503.
Antiviral treatment was
associated with a 38% lower risk
for ischemic stroke
Antiviral treatment was
associated with a 23% lower risk
for ACS
Large Taiwanese chronic HCV cohort study: 12,384 patients treated with
pegIFN/RBV and 24,768 untreated matched controls were followed up for a
mean of 3.3 years and 3.2 years, respectively
Follow-up (years)
2
1
0
1.5
0.5
0 1 2 3 4 5 6 7 8
Cu
mu
lati
ve i
ncid
en
ce (
%) Untreated
cohort Treated cohort
Ischemic stroke, p=0.001
Follow-up (years)
3
1
0
2
0 1 2 3 4 5 6 7 8
Cu
mu
lati
ve i
ncid
en
ce (
%) Untreated cohort
Treated cohort
Acute coronary syndrome,
p=0.027
Treatment of HCV Is Associated with Reduced
Risk for End Stage Renal Disease
Hsu YC, et al. Gut 2015; 64:495–503;
Large Taiwanese prospective chronic HCV cohort study: 12,384 patients treated
with pegIFN/RBV and 24,768 untreated matched controls were followed up for a
mean of 3.3 years and 3.2 years, respectively
Follow-up
(years)
1.5
0.9
0.6
0.3
0
1.2
0 1 2 3 4 5 6 7 8
Cu
mu
lati
ve i
ncid
en
ce (
%)
Untreated cohort
Treated cohort
End-stage renal disease,
p<0.001
Pre-Treatment Evaluation
• Quantitative PCR for HCV RNA
• Genotype
• Exclusion of other liver diseases (HBV, NAFLD)
• Ensuring HAV, HBV immunity
• Medications
• Comorbidity assessment
• Assessment of level of fibrosis remains essential
– Liver biopsy is OUT
– Noninvasive tests are IN
• Blood tests (APRI, FIB-4, Fibrosure, Hepascore, etc)
• Elastography (e.g. Fibroscan, ARFI, MRI)
• HCC screening w/advanced fibrosis/cirrhosis
• Varices screening for cirrhotics
Genotype 1 Regimens
AASLD/IDSA Guidelines
Updated October 2016
hcvguidelines.org
AASLD/IDSA: Recommended and Alternative Regimens for GT1 Without Cirrhosis
No Distinction Between Naïve & Experienced
Nucleotide No nucleotide
“Recommended” “Alternative”
Population LDV/SOF SOF
+ VEL
DCV
+ SOF
SMV
+ SOF GZR/EBR OBV/PTV/RTV
+ DSV
GT1a
12 wks (8 wks if
HCV RNA<6M
IU/ml, non-AA,
no HIV)
12 wks 12 wks 12 wks
12 wks
16 wks +
RBV†
12 wks + RBV
GT1b
12 wks (8 wks if
HCV RNA<6M
IU/ml, non-AA,
no HIV)
12 wks 12 wks 12 wks 12 wks 12 wks
†If NS5A RAVs present (GT1a only)
AASLD/IDSA. hcvguidelines.org. Apirl 2017.
AASLD/IDSA: Recommended and Alternative Regimens for GT1 with Compensated Cirrhosis
Nucleotide No nucleotide
“Recommended” “Alternative”
Population LDV/SOF SOF
+ VEL
DCV
+ SOF
SMV
+ SOF GZR/EBR OBV/PTV/RTV
+ DSV
GT1a
- Naive
- PR exp
12 wks
12 wks
+ RBV
or
24 wks
w/o RBV
12 wks
12 wks
24 wks
± RBV
24 wks
± RBV
24 wks
± RBV*
24 wks
± RBV*
12 wks
16 wks
+ RBV†
12 wks
16 wks
+ RBV†
24 wks + RBV
24 wks + RBV
*Not w/Q80K
†If NS5A RAVs present.
AASLD/IDSA. hcvguidelines.org. Apirl 2017.
AASLD/IDSA: Recommended and Alternative Regimens for GT1 with Compensated Cirrhosis
Nucleotide No nucleotide
“Recommended” “Alternative”
Population LDV/SOF SOF
+ VEL
DCV
+ SOF
SMV
+ SOF GZR/EBR OBV/PTV/RTV
+ DSV
GT1b
- Naive
- PR exp
12 wks
12 wks
+ RBV
or
24 wks
12 wks
12 wks
24 wks
± RBV
24 wks
± RBV
24 wks
± RBV*
24 wks
± RBV*
12 wks
12 wks
12 wks
12 wks
*Not w/Q80K
†If NS5A RAVs present.
AASLD/IDSA. hcvguidelines.org. April 2017.
The Most Recently Approved Regimen
in the US (June 2016)
Sofosbuvir/Velpatasvir
ASTRAL-1: SOF/VEL FDC for 12 Weeks in G1, 2, 4, 5, 6
Patients with and Without Cirrhosis: ASTRAL-1 Study
• Velpatasvir (VEL, GS-5816) is a pangenotypic HCV NS5A inhibitor
• GT3 pts evaluated in separate study
• 19% cirrhosis, 32% treatment-experienced
SV
R12*
(%)
99 98 99 100 100 97 100
0
25
50
75
100
Overall G1a G1b G2 G4 G5 G6
618/
624
206/
210
117/
118
104/
104
116/
116
34/
35
41/
41
*HCV RNA <15 IU/mL
Feld JJ, Jacobson IM, Hezode C, et al. N Engl J Med. 2015. Dec 31;373(27):2608-17.
Genotype 2
ASTRAL-2: SOF/VEL FDC for 12 Weeks Compared to SOF + RBV for 12 Weeks in GT2 Patients
• 266 patients with G2 HCV infection in
the US were randomized and treated
– 134 with SOF/VEL
– 132 with SOF + RBV
• 59% male
• 88% white
• 38% IL28B CC
• 15% prior treatment failure
• 14% cirrhosis
Wk 0 Wk 12 Wk 24
SVR12 SOF/VEL
SVR12 SOF + RBV
99 94
0
20
40
60
80
100
SOF/VEL SOF + RBV
SV
R1
2 (
%)
133/134 124/132
p=0.018
1 LTFU 6 relapses
2 LTFU
SVR12
Sulkowski M, et al. AASLD. 2015. San Francisco. #205; Foster GR, Afdhal N, Roberts SK, et al. N Engl J Med. 2015 Dec 31;373(27):2608-17.
ASTRAL-2: SOF/VEL FDC for 12 Weeks Compared to SOF + RBV for 12 Weeks in GT2 Patients
• 266 patients with G2 HCV infection in
the US were randomized and treated
– 134 with SOF/VEL
– 132 with SOF + RBV
• 59% male
• 88% white
• 38% IL28B CC
• 15% prior treatment failure
• 14% cirrhosis
Wk 0 Wk 12 Wk 24
SVR12 SOF/VEL
SVR12 SOF + RBV
99 94
0
20
40
60
80
100
SOF/VEL SOF + RBV
SV
R1
2 (
%)
133/134 124/132
p=0.018
1 LTFU 6 relapses
2 LTFU
SVR12
SOFOSBUVIR + RIBAVIRIN SHOULD NOT BE USED FOR GT2
Sulkowski M, et al. AASLD. 2015. San Francisco. #205; Foster GR, Afdhal N, Roberts SK, et al. N Engl J Med. 2015 Dec 31;373(27):2608-17.
Genotype 3
ASTRAL-3: SOF/VEL FDC for 12 Weeks Compared to SOF + RBV for 24 Weeks in G3 HCV Infected Patients
98 93 91 89 90
73 71
58
0
20
40
60
80
100
160 163
40 43
31* 34
33 37
141 156
33 45
22 31
22 38
Cirrhosis No Yes
Treatment-Naive Treatment-Experienced
No Yes
SOF/VEL SOF + RBV
84% No BL
NS5A RAVs n=231
16% BL NS5A RAVs
n=43
n=274 97%
SVR12
225/
231
88%
SVR12
38/
43
Resistance Analysis
*
*One reinfection: 94% without this patient
Mangia A, et al. AASLD. 2015. San Francisco. #249; Foster GR, Afdhal N, Roberts SK, et al. N Engl J Med. 2015;373:2608-17.
Management of Patients with Genotype 3
Trt
Experience Cirrhosis? Y93H RAV?
Recommended
Regimens
Naive No Testing not
recommended
Naive Yes No
Naive Yes Yes
PegIFN/RBV No No
PegIFN/RBV No Yes
PegIFN/RBV Yes --
AASLD/IDSA. HCV Guidance. April 2017.
Management of Patients with Genotype 3
Trt
Experience Cirrhosis?
Y93H
RAV? Recommended Regimens
Naive No -- • 12 wks DCV + SOF
Naive Yes No • 24 wks DCV + SOF ± RBV
Naive Yes Yes • 24 wks DCV + SOF + RBV
PegIFN/RBV No No • 12 wks DCV + SOF
PegIFN/RBV No Yes • 12 wks DCV + SOF + RBV
PegIFN/RBV Yes -- • 24 wks DCV + SOF + RBV
AASLD/IDSA. HCV Guidance. April 2017.
Management of Patients with Genotype 3
Trt
Experience Cirrhosis?
Y93H
RAV? Recommended Regimens
Naive No -- • 12 wks SOF/VEL
Naive Yes No • 12 wks SOF/VEL
Naive Yes Yes • 12 wks SOF/VEL + RBV
PegIFN/RBV No No • 12 wks SOF/VEL
PegIFN/RBV No Yes • 12 wks SOF/VEL + RBV
PegIFN/RBV Yes -- • 12 wks SOF/VEL + RBV
AASLD/IDSA. HCV Guidance at hcvguidelines.org April 2017.
Decompensated Cirrhosis
SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhotics: Genotypes 1 and 4, Childs-Pugh B and C
87 87 86 89 89 90
0
20
40
60
80
100
SV
R12 (
%)
LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks
CPT B CPT C Overall
26/30 19/22 18/20 24/27 45/52 42/47
Charlton M, et al. Gastroenterology. 2015;149:649-659.
Ledipasvir + Sofosbuvir + Ribavirin in Decompensated
Cirrhotics: Genotypes 1 and 4, Childs-Pugh B and C
Changes in MELD Score
-6
-4
-2
0
2
4
-6
-4
-2
0
2
4
n=5 n=5 n=2 n=3
(-8)
(+10)
CPT B CPT C
12 wk (n=30) 24 wk (n=29) 12 wk (n=23) 24 wk (n=26)
Flamm SL, et al. AASLD. 2014. Boston. #239.
SOF/VEL FDC for Treatment of HCV in Patients with Decompensated Liver Disease: Phase 3 ASTRAL-4 Study
• 267 treatment naive or experienced G1–6 with Child B cirrhosis
Wk 0 Wk 12 Wk 24 Wk 36
SVR12
SOF/VEL n=90
SVR12
SOF/VEL n=90
SVR12
SOF/VEL + RBV n=87
Charlton MR, et al. AASLD. 2015. San Francisco. #LB-13; O’Leary J, et al. EASL. 2016. Barcelona. #SAT-169.
ASTRAL-4: SOF/VEL FDC for Treatment of HCV in Patients with Decompensated Liver Disease
Safety
• d/c due to AE 3%; death 3% (9)
• AE more frequent with RBV
• Fatigue (29%); nausea (23%); HA (22%);
anemia (13%; 31% in RBV arm)
• RBV dose: Hb <10 = 23%; Hb <8.5 = 7%
• RBV decreased in 37% and d/c in 17%
• Bili <3 x ULN
83 88
50
100 94 96
85
100
88 94
50
86
0
20
40
60
80
100
Overall G1 G3 G2, 4, 6
SVR24 rates (%)
75/
90
82/
87
79/
90
60/
68
65/
68
67/
71
7/
14
11/
13
6/
12
G2:
4/4
G4:
4/4
G2:
4/4
G4:
2/2
G2:
4/4
G4:
2/2
G6:
1/1
- 1 1 - - - 6 1 4 - - - - - - - - - 1 - 1 - - 1
BT - 1 1 - - - Relapse 1
1 2 7 5 1 3
LTFU 1 - 1 1 - 1 Death 3 2 2 2 2 -
Charlton MR, et al. AASLD. 2015. San Francisco. #LB-13; O’Leary J, et al. EASL. 2016. Barcelona. #SAT-169.
What Therapy Should Be Used for Decompensated Cirrhotics?
1http://www.fda.gov/Drugs/DrugSafety/ucm468634.htm; 2hcvguidelines.org. Feb 24; 32016. EASL Recommendations. J Hepatol. 2016.
1. Only regimens containing an NS5A inhibitor and polymerase inhibitor
should be used for decompensated cirrhotic patients
2. Protease inhibitors should not be used in decompensated cirrhotics
because they accumulate to potentially toxic levels
3. Decompensated cirrhotics should be treated at a transplant
center or in close coordination with a transplant center
Renal Failure
C-SURFER Study: CKD Stage 4/5
Grazoprevir + Elbasvir N=122
Placebo N=101
12 weeks
Active treatment
• 55% on dialysis
• 55% with diabetes
• 52% GT1a, 48% GT1b
• 6% cirrhosis
Roth D, et al. Lancet. 2015. Oct 17;386(10003):1537-45.
66%
90%
100% 100% 99%
60%
95% 100% 99% 98%
0%
20%
40%
60%
80%
100%
TW2 TW4 TW12 FW4 FW12(SVR12)
Immediatetreatment group
Deferredtreatment group
C-SURFER: On Treatment Virologic Response Immediate and Deferred Treatment Arms
*Efficacy is presented for the modified full analysis set population (mFAS).
Roth D, et al. Lancet. 2015. Oct 17;386(10003):1537-45.
81
/122
109
/121
119
/119
118
/118
115
/116
61
/101
96
/101
101
/101
100
/101
97
/99
LDV/SOF for 12 or 24 Weeks in Kidney Transplant Recipients with Chronic G1 or 4 HCV Infection
100 100 100 96 96 100
0
20
40
60
80
100
G1 G4
SV
R12 (
%)
51/
51 6/6 4/4
Overall
51/
53* 57/
57
55/
57*
*2 lost to follow-up: NO VIROLOGIC FAILURES
Colombo M, et al. EASL. 2016. Barcelona. #GS13.
New Paradigm of HCV Therapy for Renal Failure Patients
Past:
– Difficult to use interferon + ribavirin in renal failure
– Renal transplantation historically withheld for HCV+ patients with
hepatic fibrosis (“we won’t transplant till HCV cured”)
• Concern about progression of fibrosis post-transplant
New Paradigm of HCV Therapy for Renal Failure Patients
Past:
– Difficult to use interferon + ribavirin in renal failure
– Renal transplantation historically withheld for HCV+ patients with
hepatic fibrosis (“we won’t transplant till HCV cured”)
• Concern about progression of fibrosis post-transplant
Present
– Effective and safe DAA therapy available for renal failure
patients
– Non-renal transplant candidates should be offered treatment
– If wait list is much shorter for an HCV+ kidney, may be better to
proceed with transplant and treat the HCV after transplant
New Paradigm of HCV Therapy for Renal Failure Patients
Past:
– Difficult to use interferon + ribavirin in renal failure
– Renal transplantation historically withheld for HCV+ patients with
hepatic fibrosis (“we won’t transplant till HCV cured”)
• Concern about progression of fibrosis post-transplant
Present
– Effective and safe DAA therapy available for renal failure
patients
– Non-renal transplant candidates should be offered treatment
– If wait list is much shorter for an HCV+ kidney, may be better to
proceed with transplant and treat the HCV after transplant
Future
– Transplant HCV- patients with HCV+ kidneys? Being studied
HCV Therapy: Almost at the Summit… But Still Climbing
The Quest: Pangenotypic regimens that cover resistant variants
associated with first generation NS5A and protease inhibitors
HCV Therapy: Almost at the Summit… But Still Climbing
The Quest: Pangenotypic regimens that cover resistant variants
associated with first generation NS5A and protease inhibitors
Second Generation Regimens
Protease
Inhibitor
NS5A
Inhibitor
Nucleotide
Polymerase
Inhibitor
Glecaprevir Pibrentasvir
GS-9857 Velpatasvir Sofosbuvir
Grazoprevir Ruzasvir Uprifosbuvir
+
+
+
+
+
Phase 3 Trial of SOF/VEL/VOX for 8 Weeks vs SOF/VEL for 12 Weeks in DAA-Naive GT1–6: POLARIS-2 Study
SOF/VEL/VOX n=501
SOF/VEL n=440
0 8 12 Wk
SVR12
SVR12
20 24
Jacobson IM, et al. AASLD. 2016. Boston. #LB-12.
POLARIS-2: Efficacy
95 98
0
20
40
60
80
100
SVR12, %
476/501
SOF/VEL/VOX
8 Weeks
21 relapses 4 LTFU
SOF/VEL
12 Weeks
432/440
3 relapses 1 DC due to AE
4 LTFU
Failed to meet
non-inferiority endpoint
Only 1/21 relapsers had treatment-
emergent resistant variants
Proportional difference -3.4 (-6.2% to -0.6%) noninferiority not met; error bars represent 95% confidence intervals.
Jacobson IM, et al. AASLD. LB-12.
POLARIS-2: SVR12 by Genotype (GT 1)
95 93
92 97 98 98 99 97
0
20
40
60
80
100
Overall 1 1a 1b
SV
R1
2, %
SOF/VEL/VOX 8 weeks, n=501 SOF/VEL 12 weeks, n=440
Overall GT 1a GT 1b GT 1
476
501
155
169
61
63
432
440
170
172
57
59
217
233
228
232
21
relapses
4 LTFU
3
relapses
1 W/C
1 LTFU
14
relapses
1 relapse
1 LTFU
2 relapses
1
LTFU
16
relapses
1
relapse
2 LTFU
2 of 2 patients (100%) with GT 1 Other achieved SVR12 (1 each in SOV/VEL/VOX and SOF/VEL arm); Error bars represent 95% confidence intervals.
POLARIS-2: SVR12 by Cirrhosis Status
Error bars represent 95% confidence intervals.
96 98
0
20
40
60
80
100
No Cirrhosis
N=767
394/411
SOF/VEL/VOX
8 Weeks
14 relapses 3 LTFU
SOF/VEL
12 Weeks
349/356
2 relapses 4 LTFU
1 DC due to AE
91 99
0
20
40
60
80
100
Cirrhosis
N=174
82/ 90
SOF/VEL/VOX
8 Weeks
7 relapses 1 LTFU
SOF/VEL
12 Weeks
83/ 84
1 relapse
POLARIS-2: AEs in >10% of Patients
Patients, n (%)
SOF/VEL/VOX
8 weeks
n=501
SOF/VEL
12 weeks
n=440
Headache 134 (27) 99 (23)
Fatigue 106 (21) 90 (20)
Diarrhea 88 (18) 32 (7)
Nausea 80 (16) 40 (9)
SOF/VEL/VOX 12 Weeks in NS5A Inhibitor-Experienced GT1–6 patients: Phase 3 POLARIS-1 Study
Placebo
SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC
0 4 8 12
1:1
Time (weeks)
SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC
G2–6 (n=152)
NS5A inhibitor-
experienced
G1 (n=262)
NS5A inhibitor-
experienced
46% cirrhosis
Bourlière M, et al. AASLD. 2016. Boston. #194.
SOF/VEL/VOX 12 Weeks in NS5A Inhibitor-Experienced GT1–6 patients: Phase 3 POLARIS-1 Study
Placebo
SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC
0 4 8 12
1:1
Time (weeks)
SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC
G2–6 (n=152)
NS5A inhibitor-
experienced
G1 (n=262)
NS5A inhibitor-
experienced
96
0
20
40
60
80
100
SV
R12,
%
253/263
6 relapses 1 on-tx failure
2 withdrew consent 1 LTFU
46% cirrhosis
Bourlière M, et al. AASLD. 2016. Boston. #194.
SOF/VEL/VOX 12 Weeks in NS5A Inhibitor-Experienced GT1–6 patients: Phase 3 POLARIS-1 Study
Placebo
SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC
0 4 8 12
1:1
Time (weeks)
SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC
G2–6 (n=152)
NS5A inhibitor-
experienced
G1 (n=262)
NS5A inhibitor-
experienced
96
0
20
40
60
80
100
SV
R12,
%
253/263
6 relapses 1 on-tx failure
2 withdrew consent 1 LTFU
99 93
0
20
40
60
80
100
No Cirrhosis Cirrhosis
SV
R12,
%
140/142 113/121
1 withdrew consent 1 LTFU
6 relapses 1 on-tx failure
1 withdrew consent
46% cirrhosis
Bourlière M, et al. AASLD. 2016. Boston. #194.
POLARIS-3: Phase 3 Trial of SOF/VEL/VOX for 8 Weeks and
SOF/VEL for 12 Weeks for GT3 HCV Infection and Cirrhosis
SOF/VEL/VOX n=110 G3
Cirrhosis SOF/VEL n=109
0 8 12 Week
SVR12
SVR12
20 24
96 96
0
20
40
60
80
100
SVR12
106 110
SOF/VEL/VOX
8 Weeks
2 relapses 1 withdrew consent
1 death
SOF/VEL
12 Weeks
105 109
1 on-treatment failure 1 relapse
1 discontinued due to AE 1 LTFU
Foster GR, et al. AASLD. 2016. Boston. #258.
TakeAway Points From POLARIS Studies
• Triplet regimen very effective when given for 8 weeks but
probably will not replace current 12 week regimens
(failed to meet noninferiority vs SOF/VEL for 12 weeks)
• Triplet regimen for 12 weeks very promising as “rescue”
for DAA failure patients
• Very effective regimen for GT3
ENDURANCE-1, 2, 4 Studies: Efficacy of
GLE/PIB for Treating GT1, 2, 4, 5, 6 HCV
1. Zeuzem S, et al. AASLD 2016. Abstract 253.
2. Kowdley KV, et al. AASLD 2016. Abstract 73.
3. Asselah T, et al. AASLD 2016. Abstract 114.
100
80
60
40
20
0
SV
R1
2 (
%)
99.1
*
99.7
* 99
332/
335
331/
332
195/
196
8 Wks 12 Wks
120/
121
12 Wks
ENDURANCE-1
(GT1)[1]
ENDURANCE-2
(GT2)[2]
ENDURANCE-4
(GT4-6)[3]
99
12 Wks
No cirrhosis
ENDURANCE-3: Glecaprevir/Pibrentasvir 8
or 12 Wksin GT3 HCV Without Cirrhosis
Foster GR, et al. EASL 2017. Abstract GS-007.
95 95 97
0
20
40
60
80
100
G/P 8 wks G/P 12 wks DCV/SOF 12 wks
149/157 222/223 111/115
Arms A and B not inferior to C
EXPEDITION-1: Glecaprevir/Pibrentasvir in
GT1, 2, 4, 5, or 6 HCV and Compensated
Cirrhosis, 12 Weeks
Forns X, et al. EASL 2017. Abstract GS-006. ClinicalTrials.gov. NCT02642432.
10
0
80
60
40
20
0
SV
R12
(%
)
All Pts
1
145/
146
89/
90
31/
31
7/
7
99 99 1000 100
2/
2
2 4 5 6
Genotype
100 100
16/
16
Glecaprevir + Pibrentasvir for Prior DAA Failures, n=50: Genotype 1, 12 Weeks
95 95
0
20
40
60
80
100
Arm A Arm B Arm CABT-493 (mg) 200 300 300
ABT-530 (mg) 80 120 120
SV
R12
(%)
mIT
T
100
Poordad F, et al. EASL. 2016. GS-11.
6/6 20/21 19/20
Management of Patients After SVR
• Follow patients till SVR48
• HCC screening continues in F3 or F4
• Fibroscan, serum markers may improve but not reliable
for decisions re: d/c of HCC screening
• Can d/c variceal screening if no varices prior to
treatment
• Continue surveillance, treatment as needed in patients
who received primary prophylaxis for varices or
previously bled
• No alcohol consumption with advanced fibrosis/cirrhosis
Summary
• We are now in an era of highly effective interferon free
treatment
• Historically “difficult to treat patients” are no longer
considered difficult to treat
• HIV coinfected patients have similar efficacy, must
be mindful of drug-drug interactions
• PWID should be treated with appropriate avaliable
expertise in addiction medicine w/harm reduction
• There is significant fibrosis regression, reduction in
liver complications, and all-cause mortality post-SVR
• There is no justification for withholding treatment from
HCV infected patients regardless of degree of fibrosis
• Post-SVR patients with advanced fibrosis or cirrhosis
must be monitored for liver cancer
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