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Treatment of HCV in Patients with Cirrhosis
Norah Terrault, MD, MPH
Professor of Medicine and Transplant Surgery
University of California San Francisco
SVR and All-Cause Mortality Benefits in Cirrhotics Treated With IFN-Based Therapy
van der Meer AJ et al. JAMA. 2012;308(24):2584-2593.
0 1 2 3 4 5 6 7 8 9 10
10
20
30
With SVR
Without SVR
P < 0.001
All-cause Mortality
Time (years)
All-
cau
se M
ort
alit
y (%
)
0 1 2 3 4 5 6 7 8 9 10
10
20
30
Time (years)
With SVR
Without SVR P < 0.001
0
Hepatocellular Carcinoma
Hep
ato
cellu
lar
Car
cin
om
a (%
)
0 1 2 3 4 5 6 7 8 9 10
10
20
30
Time (years)
With SVR
Without SVR
P < 0.001
Liver Failure
Live
r Fa
ilure
(%
)
0
0 1 2 3 4 5 6 7 8 9 10
10
20
30
Time (years)
P < 0.001
With SVR
Without SVR
Liver-related Mortality or Liver Transplantation
Live
r-re
late
d M
ort
alit
y o
r Li
ver
Tran
spla
nta
tio
n (
%)
0
75% Reduction in Mortality in Treated Patients with Cirrhosis
Meta-Analysis of those with SVR vs Non-SVR
Simmons B, CID 2015;61; September 1 IFN-based therapy
Unique Aspects of Treating Patients with Cirrhosis
Need for treatment is more urgent, especially if decompensated
Treatment options become more limited as patient transitions from compensated decompensated cirrhosis
SVR rates influenced by cirrhosis severity
CP-A > CP-B >> CP-C
Tolerability and safety need closer scrutiny
Concurrent liver and renal dysfunction may be present
Consequences of treatment failure may be greater
DAA Primary Metabolic Pathway
Suitable in Patients With Cirrhosis CP-A CP-B CP-C
Suitable if Renal Impairment
Sofosbuvir ± Ledipasvir
Renal Yes Yes
Yes
Not if CrCl < 30 mL/min
Daclatasvir Hepatic Yes Yes Yes Yes, but not studied in dialysis
Simeprevir Hepatic Yes (Yes) No Not if CrCl < 15 mL/min
Ombitasvir/Paritaprevir/r
Hepatic Yes No No Yes but not if dialysis
Dasabuvir Hepatic Yes No No Yes but not if dialysis
Elbasvir/grazoprevir
Hepatic Yes No No Yes
Ribavirin Renal Yes Yes Yes Yes, adjusted
Bifano M, et al. AASLD 2011. Abstract 1362. Garimella K, et al. Clin Pharm 2014. P43. Sofosbuvir [package insert]. Simeprevir [package insert]. Khatri A, et al. AASLD 2012. Abstract 758. German et al. AASLD 2013. Abstract 467. Kirby R, et al. 8th International Workshop on Clinical Pharmacology of Hepatitis Therapy PO20
Drug Options in Patients with Cirrhosis
General Themes in the Treatment of Patients with Cirrhosis
More frequent need for:
Use of ribavirin and/or
Extension of therapy
Important modifiers of SVR in this population
Presence of baseline RAVs
Severity of portal hypertension
Concurrent renal dysfunction reduces treatment options further
If decompensated cirrhosis with CrCl <30 mL/min no treatment options
Genotype 1 populations
Daclatasvir +
sofosbuvir
Ledipasvir +
sofosbuvir
Paritaprevir/r +
ombitasvir +
dasabuvir
Simeprevir +
sofosbuvir
Elbasvir +
grazoprevir
No prior treatment
Alternative +/-RBV 24 wks
Recommended, 12 wks
Alternative + RBV 24 wks
Alternative +/-RBV 24 wks
Recommended if no RAVs, 12 wks
Alternative if RAVs,16 wks+RBV
PEG/RBV failures
Alternative +/-RBV 24 wks
Recommended No RBV, 24 wks + RBV, 12 wks
Alternative + RBV 24 wks
Alternative +/-RBV 24 wks
Recommended if no RAVs, 12 wks
Alternative if RAVs,16 wks+RBV
SOF/RBV or SOF/PEG/RBV failures
Recommended + RBV 24 wks
PEG/RBV + PI failures
Recommended +/-RBV 24 wks
Recommended No RBV, 24 wks + RBV, 12 wks
Recommended No RAV, 12wk+RBV RAVs,16 wks+RBV
www.hcvguidelines.org
Genotype 1A with Compensated Cirrhosis
Genotype 1 populations
Daclatasvir +
sofosbuvir
Ledipasvir +
sofosbuvir
Paritaprevir/r +
ombitasvir +
dasabuvir
Simeprevir +
sofosbuvir
Elbasvir +
grazoprevir
No prior treatment or PEG/RBV failures
Alternative +/-RBV 24 wks
Recommended No RBV, 24 wks + RBV, 12 wks
Recommended 12 wks
Alternative +/-RBV 24 wks
Recommended 12 wks
SOF/RBV or SOF/PEG/RBV failures
Recommended + RBV, 24 wks
PEG/RBV + PI failures
Recommended +/-RBV 24 wks
Recommended No RBV, 24 wks + RBV, 12 wks
Recommended 12 wks + RBV
www.hcvguidelines.org
Genotype 1B with Compensated Cirrhosis
Total
Treatment
Naïve
Treatment
Experienced
Overall SVR12
Duration 12 wk
24 wk
Regimen LDV/SOF
LDV/SOF + RBV
Duration/
± RBV
LDV/SOF 12 wk
LDV/SOF + RBV 12 wk
LDV/SOF 24 wk
LDV/SOF + RBV 24 wk
96% 98% 95%
95% 97% 94%
98% 99% 98%
95% 96% 95%
97% 99% 96%
92% 96% 90%
96% 98% 96%
98% 97% 98%
100% 100% 100%
SVR12, %
LDV/SOF ± RBV for 12 vs 24 Weeks in Compensated Cirrhotics: Pooled Analysis
Reddy R et al, Hepatology. 2015 Jul;62(1):79-86
Total
Treatment
Naïve
Treatment
Experienced
Overall SVR12
Albumin
(g/dL)
<3.5
≥3.5
Platelets
(x 103/µL)
<75
≥75 – <100
≥100 – <125
≥125
FibroScan >12.5 – ≤20
>20
Is SVR12 Influenced by Severity of Portal Hypertension?
96% 98% 95%
99%
96%
10
98%
95%
99%
84% 90%
100%
98%
98%
100%
100%
82%
98%
93%
98%
99%
95%
SVR12, %
96%
97% 95%
98%
98%
95%
Reddy R et al, Hepatology. 2015 Jul;62(1):79-86
11
26/27 65/68
12 weeks 24 weeks
SVR
12 (
%)
10/10 27/27 8/9 19/19
Studies included for analysis: LDV/SOF 12 Wks: GS-US-334-1274 (Bleeding Disorder), GS-US-337-0102 (ION-1), GS-US-337-0113 (Japan 1), GS-US-337-0115 (ION-4), GS-US-337-0122 (ELECTRON-2), GS-US-337-0131(China), GS-US-337-1406; LDV/SOF+RBV 12 Wks: GS-US-337-0102 (ION-1), GS-US-337-0113 (Japan 1), GS-US-337-0122 (ELECTRON-2); LDV/SOF 24 Wks: GS-US-337-0102 (ION-1), GS-US-334-1274 (Bleeding Disorder)
Treatment Naive Treatment Experienced
12 weeks 24 weeks
The largest impact of RAVs on treatment outcome was observed in
patients with cirrhosis treated for 24 weeks of LDV/SOF (and no ribavirin)
Zeuzem S, Abstract 91
Efficacy of LDV-SOF in Patients with and without NS5A RAVs at Baseline
With cirrhosis
LDV-SOF in Patients with Cirrhosis
LDV-SOF for 12 weeks suitable for treatment naïve group
LDV-SOF plus RBV for 12 weeks if:
Treatment experienced
Other potential groups to consider:
Baseline RAVs present
Platelet count <75K
LDV-SOF for 24 weeks if:
Above groups but ribavirin ineligible
Summary
Efficacy of EBR-GZR in Treatment of Patients with Cirrhosis (N=402)
HCV genotype 1, 4 and 6, compensated CP-A cirrhosis Cirrhosis defined by biopsy, Fibroscan, or APRI + Fibrotest Included treatment duration of 12, 16, 18 weeks
Jacobson I, AASLD 2015, Abstract 42
Jacobson I, AASLD 2015, Abstract 42
Patients Treated with EBR-GZR with Cirrhosis: Treatment Naïve: Pooled Analysis
Jacobson I, AASLD 2015, Abstract 42
Patients Treated with EBR-GZR with Cirrhosis: Treatment Experienced
Prevalence and Impact of Baseline NS5A RAVs in Patients Treated with
EBR-GZR Jacobson I, AASLD 2015, LB-22
Prevalence of NS5A RAVs = 20%
EBR RAVs=~5% TN/relapsers
EBR RAVs=~10% if TE non-responders
GT1B: minimal impact of baseline EBR RAVs
GT1A:
12 wks EBR/GZR 16/18 wks EBR/GZR + RBV
Severity of Portal Hypertension Not Associated with SVR in Cirrhotics
Jacobson I, AASLD 2015, Abstract 42
Treatment regimens primarily driven by sub-genotype and presence of baseline RAVs
Cirrhosis and prior treatment experience appear to be less important
Genotype 1B and Genotype 1A without RAVs
12 weeks and no RBV
Genotype 1A with RAVs*
16 weeks plus RBV
EBR-GZP in Patients with Cirrhosis Summary
* baseline high fold-change
NS5A RAVs are M28, L30,
L31, and Y93
PTV/RTV + DSV for 12 Wks in Genotype 1B Patients with Cirrhosis
Characteristic N=60
White race 87%
Age, median 60.5 yrs
IL28B nonCC 83%
Experienced NR Relapser/VBT
55% 30% 8%
Fibroscan >20 49%
Platelets<90K 21%
Albumin<3.5 17%
Varices 12%
Feld J, J Hepatol 2016;64:301-7
TURQUOISE III
Treatment of Genotype 1 Cirrhosis
5 different DAA combos available
2 “recommended” for genotype 1A
3 “recommended” for genotype 1B
Determination of RBV eligibility necessary
RBV increases SVR with shorter duration therapy and in those with baseline RAVs
Presence of renal dysfunction (eGFR <30 min/mL) reduces treatment options
www.hcvguidelines.org
Genotype 3 populations
Daclatasvir +
sofosbuvir
Sofosbuvir + peg-
IFN + Ribavirin
Sofosbuvir +
Ribavirin
Elbasvir +
grazoprevir +
sofosbuvir
No prior treatment Recommended ± RBV for 24
wks
Recommended 12 wks
Alternative 24 wks
Treatment experienced
Recommended + RBV for 24 wks
Recommended 12 wks
Treatment experienced, RBV ineligible
Alternative?
Genotype 3 with Compensated Cirrhosis
www.hcvguidelines.org
SVR Rates of GT3 Regimens - Cirrhotic
82% 77%
58%
69%
91% 86%
100%
86%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Naïve Experienced
SVR
12
Rat
e
SOF/RIBA x 24weeks
SOF/DCV x 12weeks
IFN/SOF/RIBA x 12weeks
SOF/DCV/RIBA x16 weeks
Leroy V, AASLD 2015:LB-3; Nelson DR, et al. Hepatology 2015;61:1127-35; Zeuzem S, et.al. NEJM 2014;370:1993-2001; Foster GR,
et.al.Gastroent.2015;149:1462-70
(Prior IFN/Ribavirin)
Not head-to-head comparisons
European Compassionate Access Program DCV + SOF ± RBV for 24 Weeks
DCV + SOF DCV + SOF + RBV
HC
V R
NA
< L
LOQ
, TD
or
TND
, %
37 42
25 29
19 19
12 15
12 14
16 20
6 8
Child-Pugh Class MELD Score Categoryb
11 13
2 2
4 5
2 2
15 17
8 9
17 17
a Excludes 4 patients with indeterminate cirrhosis status and 5 without cirrhosis; all except 1 (DCV+SOF) achieved SVR12; b Excludes 1 cirrhotic patient with missing baseline MELD data; patient discontinued therapy at Week 4 due to AE (non-SVR12).
Welzel T, AASLD 2015, Abstract 37
14
15
Non-
cirrhotic
Cirrhotic
10
11
14
14
SOF/GRZ/EBV x 8 vs 12 Weeks in GT3
Treatment-Naïve Cirrhotic and Non-Cirrhotic
mITT analysis excluded patients who discontinued early due to reasons other than virologic failure
Poordad et al. Abstract #O006, EASL 2015
Lactic acidosis in Cirrhotics Treated with Ribavirin/Sofosbuvir N=35 patients with advanced fibrosis/cirrhosis treated with
various SOF/RBV containing regimens
16 CP-A, 12 CP-B/C; 8 post-transplant
Pre-treatment During treatment
SAEs 43% 34%
Infectious complications 16% 21%
De novo or worsening decompensation
49% 39%
Renal complications 11% 21%
Lactic acidosis* 0% 14%
*Lactic acidosis more frequent in those with advanced cirrhosis and/or renal
dysfunction
Welker M, J Hepatol 2016, in press
Antiviral options are more limited
Protease inhibitors contraindicated
Concurrent renal dysfunction may limit use of sofosbuvir
SVR rates with DAA therapy in decompensated cirrhosis (CP-B/C) are generally lower than in compensated cirrhosis (CP-A)
Benefits of therapy are great but competing risk of dying before attaining benefits
Challenges with Treating Decompensated Cirrhosis
DAA Combinations Available for Decompensated Cirrhosis
Sofosbuvir + RBV
Ledipasvir-Sofosbuvir ± RBV
[Simeprevir + Sofosbuvir]
Daclatasvir + Sofosbuvir ± RBV
G2
G1,4
G1,4-6
G1-6
www.Hcvguidelines.org accessed March 1, 2016
SOF/LDV or SOF/DCV plus RBV for Decompensated Cirrhosis
ALLY-1: GT 1
DCV + SOF + RBV 12 weeks
Charlton M, Gastroenterology. 2015 Sep;149(3):649-59 Poordad F. EASL 2015. Abstract LO8. Manns M, EASL 2015
CPT
46 53
46 50
36 42
31 38
8 relapses 3 deaths
4 relapses 7 deaths
1 LTU
Achievable Endpoints with DAA Therapy in Patients with
Decompensated Cirrhosis
Reductions in MELD score
Reversal of symptoms of decompensation
Reduced rates of portal hypertension complications
Lower mortality
Delisting
SVR Associated with Fewer Cirrhosis-Related Complications
Saxena et al. AASLD 2015, Abstract #1825..
Multicenter study of patients with compensated/decompensated cirrhosis treated with SMV/SOF ±RBV for 12-24 wks; 84% achieved SVR
Compared to 269 untreated/non-SVR matched controls Median MELD=9 and CP score 6
SVR SVR
No-SVR No-SVR
Bivariate Cox Regression Analysis of Factors
Associated with Liver Transplantation / Death
Unique Clinical Issues with Treatment of Patients with Decompensated Disease Recognize the competing risk of progressive disease
and liver-related mortality
Benefits of SVR are more than viral eradication
Improvement in MELD, CP scores in majority, but most in the short term
Reversal of symptoms of decompensation in some
Wait-listed patients present special challenge
Weighing benefits of treatment vs LT
SOF/VEL for 12 weeks: SVR12 Rates in Patients with Cirrhosis
99% 100%
91%
G1-6 G2 G3
120/121
1 relapse
7 relapses
73/80
19/19
Foster G, N Engl J Med, 2015;373:2608-17.
Feld J, N Engl J Med. 2015;31;373:2599-607.
SOF/VEL + RBV for 12 weeks: SVR12 Rates in Patients with Decompensated Cirrhosis
96%
85%
100%
Curry M, N Engl J Med 2015;373(27):2618-28.
65/68
1 relapse 2 deaths
GT 2 (4/4)
GT 4 (2/2)
Treatment of Patients with Cirrhosis Take Home Messages
High priority for treatment
Benefit great if SVR achieved
More limited treatment options if decompensation
Still room for improvement in treatment regimens
Eliminate ribavirin
Options for decompensation plus renal dysfunction
Vigilance regarding safety, especially if concurrent decompensation and renal dysfunction
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