Genotype 3

Treatment of Special Populations:
Cirrhotics, Genotype 3, Renal
Failure, Posttransplant
Raymond T. Chung, MD
Associate Professor of Medicine
Director of Hepatology and Liver Center
Vice Chief, Gastroenterology
Mass General Hospital
The Rising Tide Has Lifted
Nearly All Boats
► Genotype 1
– Naïve
– Nonresponders
► Genotype 2
► Genotypes 4, 5, 6
► HCV / HIV
► Pre-liver transplant
Who’s Left Behind?
Possible Gaps
► Genotype 3
► Cirrhosis, esp. decompensated liver disease
► Renal failure
► Triple-therapy failures
Genotype 3
► Splitting, not lumping with GT2!
► Licensed: sofosbuvir + RBV x 24 weeks
► Gap in cirrhotic nonresponders
► Alternatives
– PEG/RBV/SOF
– Others
Genotypes 2,3 as Low-Hanging Fruit
►We’ve historically lumped GT3 with GT2 in IFN+RBV studies.
►Excellent SVR rates associated with PEG/RBV for GT2/3.
►Some subgroup studies have shown diminished response
rates for GT3 high viral load or cirrhosis.
►Not surprisingly, DAA efforts therefore focused principally
on GT1.
PEG-IFN a-2b/RBV vs. IFN a-2b/RBV
IFN/RBV 1000 -1200 mg/d (n=505)
100%
PEG (12 kD) 0.5 µg/kg qw / RBV 1000 -1200 mg/d (n=514)
PEG (12 kD) 1.5 µg/kg qw / RBV 800 mg/d (n=511)
†P=0.01
vs. IFN/RBV
§P=0.02
vs. IFN/RBV
42%
34%
33%
20%
47%
40%
54%
§
82%
†
80%
60%
47%
Sustained
virologic
response
79%
80%
0%
Overall
Genotype 1
Genotype 2/3
Manns et al, Lancet 2001;358:958-65
ELECTRON Trial Arms Using Sofosbuvir GT2/3
(Nuc Pol Inhibitor)
Treatment
SOF x 12W
SOF+RBV x 12W
SOF+RBV x 8W
SOF+RBV 800 x12W
Population
SVR12
GT2/3 naïve
60% (6/10)
GT2/3 naïve
100% (10/10)
GT2/3 experienced 68% (17/25)
GT2/3 naïve
64% (16/25)
GT2/3 naïve
60% (6/10)
AASLD 2012, Abstr 229
Sofosbuvir in Treatment-Naïve GT2,3 Patients
FISSION
SOF 400 mg +
RBV daily x 12 wks
PEG-2a weekly +
RBV 800 mg daily x 24 wks
97
100
78
80
67
67
SVR %
63
56
60
40
20
0
n=
253
243
Overall
70
GT2
67
183
176
GT3
Lawitz et al, NEJM April 23, 2013
Sofosbuvir in Genotype 2/3
POSITRON – Naïve with
contraindications to IFN
FUSION – Tx-experienced
SOF 400 mg + RBV daily
SOF 400 mg + RBV daily x 12 wks
100
12 weeks
100
93
80
78
60
50
%
%
73
62
61
40
40
20
20
0
0
n=
SR
Plac
GT2
GT3
207
71
109
98
94
86
80
60
16 weeks
30
0
Overall
n=
103
98
GT3
GT2
36
32
64
63
Jacobson et al, NEJM April 23, 2013
SVR12 (%)
FISSION: SVR12 by Genotype and Cirrhosis
58/59
44/54
10/11
No cirrhosis
8/13
Cirrhosis
GT2
Error bars represent 95% confidence intervals.
89/145 99/139
13/38
No cirrhosis
11/37
Cirrhosis
GT3
FUSION: SVR12 by HCV Genotype/Cirrhosis
SOF + RBV 16 weeks
SVR12 (%)
SOF + RBV 12 weeks
25/26
23/23
6/10
No cirrhosis
7/9
Cirrhosis
GT2
Error bars represent 95% confidence intervals.
14/38
25/40
5/26
No cirrhosis
14/23
Cirrhosis
GT3
Is Genotype 3 the New 1?
• Sofosbuvir (nuc pol inhibitor) pangenotypic by virtue of
conservation of NS5B active site
• Signature resistance mutation has very low fitness –
essentially no in vivo genotypic resistance found
• Higher rates of relapse
• Unfortunately, few other DAAs available to consider for
combination with sofosbuvir for GT3
Possible Reasons for Failure in GT3 HCV
• Not due to differences in IC50 for sofosbuvir for GT3
• GT3 intrinsically steatogenic
– 80% steatosis vs. 50% seen with GT1.
– HCV GT3 core protein induces intracellular lipid accumulation in
cultured and primary hepatocytes.
– Core domain II interacts with lipid droplets, key for assembly of virus.
– Y164F substitution in core II unique to GT3.
– Cells expressing HCV core substituted with Y164F had more lipid
droplet accumulation (including affinity of F for lipids).
Hourioux C, Gut 2007;56:1302-8
Qiang G, Virus Res 2009;139:127-30
Steatosis Is a Predictor of Relapse in GT3 PEG/RBV RVRs
Shah S, CGH 2011;9:688-93
Restivo L, J Viral Hep 2012;19:346-52
Linkage of GT3, Steatosis, and Impaired Antiviral Response
• Steatosis  ER stress decreased IFNAR1 expression 
impaired type I IFN signal transduction.
• IL28B unfavorable TT genotype is also associated with
steatosis, insulin resistance irrespective of viral genotype.
• GT3 NS5A also impairs IFN signaling by binding STAT1.
Gunduz F, Virol J 2012;9:143
Kumthip K, J Virol 2012;86:8581
Sofosbuvir/Ribavirin for Treatment-Naïve and
Experienced Patients with Genotype 2 or 3: VALENCE
• Phase 3 trial in Europe
– Amended to treat GT3 for 24 weeks
• Sofosbuvir/RBV for 12 weeks (GT2,
n=73) or 24 weeks (GT3, n=250)
– Cirrhosis, 14–23%
– Treatment experienced, 58%
• 12 and 24 weeks had similar
safety/tolerability
• Discontinuation due to AE, n=2
SVR12 G2 (blue), G3 (red)
100
94
87
92
75
60
50
25
27/45
0
No cirrhosis
Zeuzem et al, Liver Mtg 2013, Abstr 1085
Cirrhosis
Sofosbuvir + PEG-IFN/RBV for 12 Weeks in TreatmentExperienced Patients with Genotype 2 or 3: LONESTAR-2
• 47 patients with GT2 (n=23) or
GT3 (n=24)
– Cirrhosis, n=26 (55%)
– Prior relapse, 85%
• Single-arm, open-label SOF 400 mg
QD + PEG-IFN/RBV for 12 weeks
• Non-SVR patients
– GT2: Discontinued with quantifiable
HCV RNA, n=1
– GT3: Lost to follow-up (n=2)
Relapse, n=2
• AEs were consistent with
PEG-IFN/RBV
Lawitz et al, Liver Mtg 2013, Abstr LB-4
Daclatasvir + Sofosbuvir ± RBV x 24W: High Rates of SVR
Genotype 1a/1b HCV
100
100 100 100
100 100 100
93 100 100
60
40
20
n=
0
7d L/I
No L/I
+ RBV
100
100 100 100
94
100 100
100
88
93
80
Patients (%)
Patients (%)
80
Genotype 2/3 HCV
7d L/I
No L/I
+RBV
60
40
20
15 14 15
15 14 15
15 14 15
Wk 4
Wk 24
(EOT)
SVR24
n=
0
16 14 14
16 14 14
16 14 14
Wk 4
Wk 24
(EOT)
SVR24
Sulkowski et al, NEJM 2014;370:211-21
The Cirrhotic Patient
► Limited success seen in cirrhotics with PEG/RBV,
PEG/RBV/TVR or BOC
► Explanations:
– Structural: limited drug delivery
– Impaired innate, adaptive immunity
► Until now, no successful, safe strategies in the
decompensated cirrhotic
► How to overcome?
The Promise of Triple Therapy Does
Not Reach to All Groups
Prior
relapsers
Prior partial
responders
Prior null
responders
Pooled T12/PR48
SVR (%)
Pbo/PR48
n/N=
144/167 12/38
53/62 2/15
48/57 2/15
34/47 3/17
Stage
No, minimal
or portal
fibrosis
Bridging
fibrosis
Cirrhosis
No, minimal
or portal
fibrosis
10/18
0/5
Bridging
fibrosis
11/32
1/5
Cirrhosis
24/59 1/18
No, minimal
or portal
fibrosis
15/38
0/9
Bridging
fibrosis
7/50
1/10
Cirrhosis
Zeuzem et al, NEJM 2011;364:2417-27
SVR12
Sofosbuvir + PEG/RBV:
Phase 3 NEUTRINO Study (GTs 1,4,5,6)
n=327
n=292
35
56
Lawitz et al, NEJM April 23, 2013
Simeprevir plus Sofosbuvir ± RBV in GT1 Treatment-Naïve
and Prior-Null-Responder Patients: COSMOS
• Cohort 2 (n=84): Treatment-naïve
and null responders with METAVIR
F3-4 SMV/SOF ± RBV x 12 or 24
weeks
• SVR4 for 12-week groups only
– GT1a, 78%; Q80K, 40%
– Cirrhosis, 47%
– Null response, 54%
– SVR4 in cirrhotics: 17 of 18 (94%)
• Non-SVR patients (n=1)
– No breakthrough
– Relapse: n=1; null responder with
cirrhosis and 1a/Q80K
Jacobson et al, Liver Mtg 2013, Abstr LB-3
Pretransplant Sofosbuvir and Ribavirin to Prevent
Recurrence of HCV Infection After Liver Transplantation
• Patients with HCC meeting
MILAN criteria
– CTP ≤ 7; MELD < 22
• 61 patients were treated
with SOF/RBV for up to 48
weeks; 44 transplanted
– At transplant, HCV RNA <
LLOQ in 93%
– Posttransplant SVR12 in 23 of
37 (62%)
• SAEs, 18% – not related to
SOF/RBV
Curry et al, Liver Mtg 2013, Abstr 213
Sofosbuvir and Ribavirin for Recurrent Hepatitis C
Infection After Liver Transplantation
• 40 patients with recurrent HCV ≥ 6
months posttransplant
–
–
–
–
MELD ≤ 17; CTP ≤ 7
Cirrhosis, n=16
GT1, n=33
Years since transplant, 4.3
• SOF 400 mg QD + RBV x 24 weeks
– Relapse in 9 patients (22.5%)
• Discontinuation due to AEs, n=2
– Anemia, n=8 (20%)
100
Virologic Response
100
100
77
75
50
25
40/40
39/39
27/35
Week 4
EOT
SVR4
0
Charlton et al, Liver Mtg 2013, Abstr LB-2
The HCV Cirrhotic
• Combinations of DAAs appear to provide the additional
potency to overcome barriers posed by the
cirrhotic/decompensated patient.
• These DAA combinations can be given safely, even in
decompensated patients.
• Can expect additional viable options:
– SOF/LDV, ABT450/r, ABT267, ABT333 ± RBV
– MK5172, MK8742 ± RBV
– DAC, ASV, BMS791325
Renal Failure
► Problems with renal clearance of SOF, RBV
► PEG poorly tolerated, requires dose reduction
► AASLD-IDSA: PEG-2a 135 µg or PEG-2b 1 µg/kg + RBV 200
mg/d, all genotypes
► Careful monitoring required
End-Stage Kidney Disease:
HCV Treatment With PEG-IFN/RBV
Author
Bruchfeld et al.
N
6
Treatment
Regimen
SVR
Withdrawal
PEG-IFN-α-2a or -2b
+ RBV
135 µg/wk (PEG-IFN-α2a) or 50 µg/wk
(PEG- α-2b), and TBV 200-400 mg/d
for 48 (GT1/4) or 24 (GT2) wks
50
33
97
14
Rendina et al.
35
PEG-IFN -α-2a + RBV
135 µg/wk (PEG-IFN), and RBV 200
mg/d for 48 (GT1) or 24 (GT non-1)
wks
Carriero et al.
14
PEG-IFN-α-2a + RBV
135 μg/wk (PEG-IFN), and RBV 200
mg/d for 48 wks
29
71
Van Leusen et al.
7
PEG-IFN-α-2a + RBV
135 μg/wk (PEG-IFN), and RBV 200 mg
qod for 48 (GT1/4) or 24 (GT2/3) wks
71
0
Hakim et al.
15
PEG-IFN-α-2a + RBV
135 μg/wk (PEG-IFN) and RBV 200
mg/wk to 3 times/wk for 48 wks
7
33
Liu et al.
35
PEG-IFN-α-2a + RBV
135 μg/wk PEG-IFN, and RBV 200
mg/d for 48 (GT1) or 24 (GT2) wks
60
Liu et al, J Gastr Hepatol. 2011;26:228-39
The Kidney Transplant Candidate
• For kidney transplant candidates, deferral of therapy until
after transplant may be prudent choice
– If liver disease stage limited
– IFN-sparing regimens make this consideration possible
– DAAs with favorable drug-drug interaction profiles
Future Treatment Options for ESKD
•
•
•
•
SMV + DCV
ABT450/r + ABT267 + ABT333
MK5172 + MK8742
DCV + ASV + BMS791325
Triple-Therapy Failures
► The new unmet need
► Resistance-associated variants against first-generation PIs
– Problem of cross-resistance
► RAVs do recede, but unclear whether retreatment with PIs
feasible
► Fortunately, sofosbuvir and additional classes available soon
Experience with Boceprevir or Telaprevir + PEG-IFN/RBV
at Academic and Community Sites: HCV-TARGET
Boceprevir
(n=262)
Telaprevir
(n=838)
60.3%
60.7%
56 (20-76)
56 (18-75)
Black race
15.7%
15.9%
Genotype 1, no subtype
22.1%
22.3%
Cirrhosis
29.8%
45%
58%
61%
41.6%
34.7%
Epoetin alfa use
41%
38%
Transfusion
10%
10%
Skin rash
32%
63%
Serious adverse events
15%
11%
Male sex
Median age, years (range)
SVR, treatment-naïve patients
Premature discontinuations
Di Bisceglie et al, Liver Mtg 2013, Abstr 41
Pts with HCV RNA <LLOQ (%)
SVR with DCV + SOF ± RBV in GT1 Patients Who
Previously Failed TVR or BOC (n=41 Noncirrhotics)
DCV + SOF (n=21)
DCV + SOF
+ RBV (n=20)
Missing
SVR4
SVR12
 1 pt missing at posttreatment (PT) Wk 12:
HCV RNA undetectable at PT Wk 4 and at PT Wk 24
Sulkowski et al, NEJM 2014;370:211-21
SOF/Ledipasvir FDC ± RBV for Patients With GT1, Including
Patients With Cirrhosis and Prior PI Failure: LONESTAR
• Treatment naïve, n=60
– SOF/LDV +/- RBV for 8
or 12 weeks
• PI virologic failure,
n=40
– Cirrhosis, n=22
– SOF/LDV ± RBV for 12
weeks
• Non-SVR, n=3
– Lost to follow-up, n=1
– Viral relapse, n=2
• No treatment
discontinuation
due to AE
Lawitz, Liver Mtg 2013, Abstr 215/1844
Summary
► Advent of DAAs has brought prosperity to nearly all HCV
subgroups.
► Remaining pockets include GT3, decompensated cirrhosis,
renal failure, triple-therapy failures.
► Forthcoming DAAs should provide enhanced success rates in
these populations.
► Main challenges in future will be multiclass DAA failures
– Role of host-targeting antivirals

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