Transcript Slide 1

HCV treatment before and
after liver transplantation
in the era of new
antivirals
Mario Angelico
Liver Unit, Università Tor Vergata, Roma
Roma, 24 Giugno 2014
Trattamento di HCV
nell’era dei nuovi antivirali
• Quali vantaggi dalle nuove terapie ?
• Stato dell’arte nel paziente in lista di attesa e
nel paziente trapiantato
Black holes in HCV and Transplantation
(2005-2012/3)
• “If possible, all cirrhotic patients with
favorable predictors who are candidates to
transplantation should be treated with
antivirals before transplant !”
• In a real scenario dual therapy is feasible in a
subset of wait-listed patients, mainly
including:
– CTP A, young, G2 (and G3), IL28b C/C, RVR
SVR prevents the development of esophageal
varices in CTP A HCV-related cirrhosis
Bruno et al, Hepatology 2010
• A 12-year prospective followup of 218 compensated
cirrhosis
• Endoscopic surveillance every
3 years
• 34 patients (22.8%) achieved
SVR. None of these developed
varices !
• Conversely, 31.8% of untreated
patients and 39.1% of treated
patients without SVR
developed varices
Long-Term Outcome After Antiviral Therapy of
Patients With Hepatitis C Virus Infection and
Decompensated Cirrhosis
Angelo Iacobellis, Francesco Perri, Maria Rosa Valvano, Nazario Caruso, Grazia Anna
Niro and Angelo Andriulli
Clinical Gastroenterology and Hepatology, (March 2011)
DOI: 10.1016/j.cgh.2010.10.036
Conclusions
• In decompensated cirrhotics, HCV clearance by therapy
is life-saving and reduces disease progression
Cumulative survival rates in decompensated
patients with or without SVR
Mean follow-up off therapy was 56 ± 19 months for the SVR group and 48 ± 17 months for no SVR
Source: Clinical Gastroenterology and Hepatology 2011; 9:249-253 (DOI:10.1016/j.cgh.2010.10.036 )
A warning from the CUPIC experience
after the introduction of first PI
• The CUPIC experience points to the alarming
impact of drug toxicity on the treatment
outcomes in cirrhotic patients, despite the
evidence that response was robust
• Independent predictors of
morbidity/mortality were platelets below
100,000 and serum albumin <3.5 g/dl.
DAAs as components of new
treatment paradigm for hepatitis C
Peg-IFN + RBV (SOC)
IFN-based
1 x DAA + SOC
2 x DAAs + SOC
IFN-free
IFN-free
2000
2013
Time
DAA=direct-acting antiviral; SOC=standard of care
2015
Prospect of
shorter
treatment
duration
for a greater
proportion of
patients
Current scenario in Italy
• Around 500/550 liver transplants in HCV infected recipients
performed in Italy each year and possibly another 500-1000 (?)
not currently eligible due to organ shortage or underreferral
• All patients are expected to recur after transplantation, with
unfavorable impact on survival and overall costs !
• Expectations to treat all cirrhotic patients prior to transplant
with all-oral regimens:
–
–
–
–
To reduce post-transplant recurrence and improve survival
To facilitate donor-recipient matching in this population*
To delay liver transplantation (expected MELD improvement)
To avoid liver transplantation (fall below MELD 15 threshold)
Sofosbuvir (SOF, GS-7977)
• HCV-specific uridine nucleotide NS5B polymerase inhibitor (chain
terminator)
• Potent antiviral activity against
HCV genotypes 1–6
• High barrier to resistance
• Once-daily, oral, 400-mg tablet
• Favorable clinical pharmacology
profile
 No food effect
 Renally cleared - limited potential for drug interactions
 No CYP3A/4 metabolism
 limited potential for drug interactions
• Well-tolerated with an excellent safety profile in clinical studies to
date (>3000 patients)
SOF Phase 3 Fibrosis Analysis
SVR12 Rates in GT 1, 4, 5, 6 (NEUTRINO)
SVR12 Rates by FibroTest Stage
(n=323)
SVR12 Rates by Biopsy Fibrosis Stage
(n=232)
F1–2
F0
91
F4
96
80
78
60
40
79
60
40
20
20
n=
0
97
F3
85
SVR12 (%)
SVR12 (%)
100
89
80
SVR12 (%)
F4
100
100
F1–2
F0
F3
16/16
16/16
124/137
124/137
34/38
34/38
32/41
32/41
76/78
101/105
n=
076/78 26/29 75/76 46/54 68/86
46/54
68/86
63/65 23/26 66/67 41/49 64/81
Treating at earlier stages of fibrosis is associated with higher response !
Patel K, et al. AASLD 2013. Washington, DC. #1093
ION-1 & ION-2
published on April 12, 2014, at NEJM.org
TURQUOISE II STUDY - published on April 12, 2014, at NEJ
Trattamento di HCV
nell’era dei nuovi antivirali
• Quali vantaggi dalle nuove terapie ?
• Stato dell’arte nel paziente in lista di attesa e
nel paziente trapiantato
2013 AASLD Meeting, Washington, oral presentation
Pretransplant Sofosbuvir and Ribavirin to
Prevent Recurrence of HCV Infection
After Liver Transplantation
Michael P. Curry, Xavier Forns, Raymond Chung, Norah Terrault, Robert Brown
Jr, Jonathan M. Fenkel, Fredric Gordon, Jacqueline O’Leary, Alexander Kuo,
Thomas Schiano, Gregory Everson, Eugene Schiff, Alex Befeler, John G.
McHutchison, William T. Symonds, Jill Denning, Lindsay McNair, Sarah
Arterburn, Dilip Moonka, Edward Gane, Nezam Afdhal
Currie et al, AASLD 2013
Study Objectives
• Primary
Prevention of HCV recurrence following orthotopic LT,
defined as post-transplant virologic response (pTVR)
at Week 12 in patients who received more than 12
weeks of treatment and undetectable HCV RNA at
transplant
• Secondary
Safety and tolerability
HCV RNA viral kinetics pre- and post-transplantation
Currie et al, AASLD 2013
Key Inclusion/Exclusion Criteria
• Inclusion criteria
 Males or females, aged =18 years, with HCC and HCV
 Standardized immunosuppressive regimen for the first 12
weeks post-transplant (tacrolimus/MMF/prednisone)
• Exclusion criteria
 Living donor liver transplantation
 Planned induction therapy with biologics
 Signs of decompensated cirrhosis
 HBV or HIV coinfection
 History of prior solid organ transplantation
 Evidence of renal impairment (CrCl <60 mL/min)
Currie et al, AASLD 2013
Study Design
• Patient population
 DDLT candidates with HCV and HCC meeting MILAN criteria
 MELD exception for HCC
 CPT =7
• Enrollment at 16 sites
 8 UNOS regions
 2 international sites
• 61 patients enrolled
• Original protocol: until LT or up to 24 weeks of treatment
with SOF 400 mg + RBV 1000-1200 mg
 Amendment: extend treatment duration to 48 weeks or LT
Currie et al, AASLD 2013
Baseline characteristics
Sofosbuvir + Ribavirin (n=61)
Male n (%)
Median Age (y) range
49 (80)
59 (46-73)
BMI <30 n (%)
43 (70)
HCV RNA >6log IU/ml
41 (67)
Genotype 1a
Genotype 1b
Genotype 2
Genotype 3
Genotype 4
24 (39)
21 (34)
8 (13)
7 (12)
1 (2)
IL28B non-CC allele
47/60 (78)
CTP A5
26 (43)
CTP A6
18 (30)
CTP A7-7
17 (28)
Median MELD score
8 (6-14)
Currie et al, AASLD 2013
Results: Post-transplant (12 weeks)
virologic results
%
93%
41/44
25/39
Pre-Transplant SOF + RBV to Prevent HCV Recurrence Post-Transplant
No Recurrence vs. Recurrence in GT 1–4
Days Continuously TND Prior to Transplant:
PTVR vs. Recurrence in GT 1–4
*
No Recurrence (n=28)
Recurrence (n=10)
1/25 patients had recurrence after
> 4 weeks continuous TND
Median days TND
• No recurrence: 95
• Recurrence: 5.5
p <0.001
0
27
50
100
150
200
250
Days with HCV RNA Continuously TND Prior to Liver Transplant
*3 patients with recurrent HCV had 0 consecutive days TND before transplant.
Curry MP, et al. AASLD 2013. Washington, DC. Oral #213
300
350
Currie et al, AASLD 2013
Adverse events
Sofosbuvir + Ribavirin, n= 61)
SAEs
11 (18)
Deaths before LTx
2 (3)
Death after Ltx
3 (5)
AEs leading to treatment
discontinuation
2 (3)
Fatigue
23 (38)
Anemia
14 (23)
Haedache
14 (23)
Nausea
10 (16)
Rash
9 (15)
Insomnia
7 (11)
Dyspnea
7 (11)
Practical considerations for the current use of
sofosbuvir in transplant candidates in Italy
 When start treatment ?
• ASAP (even before listing !)
Practical considerations for the current use of
sofosbuvir in transplant candidates in Italy
 When start treatment ?
• ASAP (even before listing !)
 How to treat patients ?
• with Peg-IFN and ribavirin, whenever feasible, but ….
• better in association with another DAA (daclatasvir or
simeprevir)
Practical considerations for the current use of
sofosbuvir in transplant candidates in Italy
 When start treatment ?
• ASAP (even before listing !)
 How to treat patients ?
• with Peg-IFN and ribavirin, whenever feasible, but ….
• better in association with another DAA (daclatasvir or
simeprevir) (ledipasvir in the near future)
 How long treat patients ?
• according to current recommendations
• at least 4 weeks prior to transplant !
• continue Sofosbuvir for additional 8 weeks after Tx (?)
EASL, 2014
Sofosbuvir Compassionate Use Program for Patients
with Severe Recurrent Hepatitis C Including Fibrosing
Cholestatic Hepatitis Following Liver Transplantation
Xavier Forns1, Martín Prieto2, Michael Charlton3, John G. McHutchison4,
William T. Symonds4, Diana Brainard4, Jill Denning4, Theo Brandt-Sarif4,
Paul Chang4, Valerie Kivett4, Robert J. Fontana5, Thomas F. Baumert6,
Audrey Coilly7, Lluís Castells8, François Habersetzer6
1Liver
Unit, IDIBAPS, CIBEREHD, Hospital Clinic, Barcelona, Spain; 2Hepatology Unit, CIBEREHD, Hospital
4Gilead Sciences, Foster
Universitari i Politècnic La Fe, Valencia, Spain; 3Mayo Clinic, Rochester, MN, USA;
City, CA, USA; 5University of Michigan, Ann Arbor, MI, USA; 6Hôpitaux Universitaires de Strasbourg, Inserm U
1110, Strasbourg, France; 7Centre Hépato-Bilaire, Hôpital Paul Brousse, Inserm UMR-S785, Villejuif, France;
8Liver Unit‒Internal Medicine Department, CIBEREHD, Hospital Universitari Vall Hebron, Barcelona
International Liver Congress 2014, London, UK
Introduction
• Hepatitis C recurrence post-transplant is universal
• Most patients will develop histological features of acute
hepatitis between 4-12 weeks (~5% fibrosing cholestatic
hepatitis)1
• Around 30% of patients will have an accelerated course with
significant fibrosis (≥ F2) one year after transplantation1
• These patients are at high risk of graft loss; survival rates fall
significantly once cirrhosis is established1
• Current therapy choices are sub-optimal
1. Crespo G, et al. Gastroenterology 2012;142:1373-83.
27
Objectives, Study Design and Analysis
• Objective
– Assess the safety and efficacy from the SOF compassionate use program by
collecting and analyzing reported data
• Inclusion criteria
– Severe recurrent hepatitis C post-transplant and likely to have less than 1
year life expectancy
• Design
– SOF 400 mg/d for 24-48 weeks plus ribavirin ± Peg-IFN
• Analysis
– Descriptive safety and efficacy
– Data presented are from 104 patients who completed or prematurely
discontinued treatment before January 1, 2014*
*Patients who were co-infected with HIV, did not have end of treatment confirmed or did not
have severe recurrence were not included in this analysis; patients receiving a liver transplant while in program
were included in safety but not efficacy analysis.
28
Results: Patient Disposition
Severe acute hepatitis/early recurrence
(<12 months from liver transplant with typical
biochemical and histological findings)
n=48
Post transplant compensated and
decompensated cirrhosis
(liver biopsy (F4) or clinical decompensation)
n=56
Early term due to AE
n=7
Liver transplant
n=12
SOF Compassionate Use Program
SOF + RBV ± PEG
n=104
Death
n=13
Completed 24-48 weeks
treatment
n=72
29
Results: Baseline Characteristics
Overall
(n=104)
Male, n (%)
Median age, y (range)
Median HCV RNA, log10 IU/mL (range)
76 (73)
55 (16-76)
8.4 (1.3-8.9)
GT, n
1/1a/1b
2/3/4
Median bilirubin, mg/dL (range)
8/29/51
1/7/8
3.1 (0.4-45)
Median albumin, g/dL (range)
3.1 (1.3-12.2)
Median INR (range)
1.3 (0.8-4.5)
Median ALT, IU/L (range)
71 (8-1162)
Median platelets, x103/µL (range)
78 (19-340)
Median MELD (range)
15 (6-43)
Median months from LT to treatment, (range)
17 (1-262)
30
Patients HCV RNA < LLOQ (%)
Results: Overall Virologic Response
Patients were excluded from this analysis if received a liver transplant (n=8 at EOT; n=12 at SVR12)
and/or no data was available (n=3 at EOT; n=7 at SVR12).
31
Results: Overall Virologic Response
8/93
4/85
4/93
13/85
Patients (%)
15/85
32
Patients (%)
Results: Clinical Outcomes
 All patients who received ≥1 dose of SOF are included
*Significant decrease in hepatic encephalopathy, improvement or disappearance of ascites, or improvement in
liver-related laboratory values.
33
Albumin (g/L)
MELD
INR
Bilirubin (mg/dL)
Results: Laboratory Tests
(Median and Interquartile Ranges)
34
Clinical Cases: Fibrosing Cholestatic Hepatitis
Patient 1 (SOF + RBV 24 Weeks)
Patient 2 (SOF + RBV 48 Weeks)
HCV RNA 8 log10 IU/mL
GGT (IU/L)
4
FU12
SOF + RBV
Treatment
•
Off
Treatment
Blirubin (mg/dL)
Bilirubin (mg/dL)
BL
Week
GGT (IU/L)
HCV RNA 8.7 log10 IU/mL
BL 4
FU12
SOF + RBV
Treatment
Off
Treatment
Viral load undetectable by Week 4 (Patient 1) and Week 12 (Patient 2) resulting
35
in SVR12
Conclusions
• Treatment with SOF + RBV ± PEG in patients with severe
recurrent HCV who have no other treatment options
resulted in:
– Higher rates of SVR than prior standard therapies
– Improved liver function tests in the majority of patients
– Improved clinical outcomes as defined by a decrease in
clinical decompensating events
• SOF + RBV for up to 48 weeks was generally safe and well
tolerated
36
Dual DAA therapy should be given early in
cirrhotic patients !
Pellicelli, Dig Liv Dis 2014
• 12 LT recipients with recurrent HCV G1 disease
enrolled in a compassionate use program with
Sofosbuvir and Daclatasvir
• Patients had decompensated cirrhosis (n=9) (mean
MELD = 22) and/or fibrosing cholestatic hepatitis
(n=3)
Dual DAA therapy should be given early in
cirrhotic patients !
Pellicelli, Dig Liv Dis 2014
• 12 LT recipients with recurrent HCV G1 disease
enrolled in a compassionate use program with
Sofosbuvir and Daclatasvir
• Patients had decompensated cirrhosis (n=9) (mean
MELD = 22) and/or fibrosing cholestatic hepatitis
(n=3)
• Half of the patients experienced SAE and 3 patients
died during treatment !
Changes in liver function in 9 patients who
completed 24 weeks of antiviral treatment
Pellicelli et al, DLD, 2014
Variables
Baseline
Week 12
Week 24
P value
MELD score mean±SD
18.5±6.6
15±5.3
15±7.4
0.2
Child-Pugh score mean±SD
9.3±1.8*
7.5±1.9
7.5±1.6*
<0.04
Albumin (gr/dL) mean±SD
3.1±0.4§
3.4±0.1
3.6±0.1§
<0.006
Total Bilirubin (mg/dL)
mean±SD
INR mean±SD
3.8±2.8
1.8±0.6
1.6±0.6
0.1
1.39±0.2
1.4±0.3
1.47±0.4
0.4
Creatinine (mg/dL) mean±SD
1.84±0.9
1.46±0.5
1.46±0.6
0.2
Platelets (x103/μL) mean±SD
97±58
87±38
84±36
0.7
Characteristics of 3 patients who died during
antiviral treatment
Pellicelli et al, DLD, 2014
Characteristics
Patient 1
Patient 2
Patient 3
Age (years) / gender
59/male
55/female
51/male
Treatment week completed
Week 10
Week 8
Week 4
Sepsis
GI bleeding
Liver failure
33
24
40
C14
B8
C12
Yes
No
No
CNI at baseline
Cyclosporine
Everolimus
Tacrolimus
last HCV RNA determination
Undetectable
Undetectable
Undetectable
Cause of death
MELD at baseline
Child-Pugh Class score
baseline
Ribavirin treatment
at
Our conclusions
• The all oral combination of sofosbuvir and daclatasvir
+/- ribavirin has potent antiviral effectiveness in
patients with severe recurrence of HCV, without
interactions with immunosuppressant drugs.
• Despite improved liver function, death and severe
disease complications occur frequently
• This potent combination must be initiated earlier
than currently allowed !
Future (imminent) perspectives
Transplant candidates with HCV infection
• The ultimate goal would be to treat all potential
transplant* candidates ASAP with a third-generation
all oral DAA combination (whichever first available):
–
–
–
–
SOF + Simeprevir
SOF + Daclatasvir
SOF + Ledipasvir
ABT-450/r + ombitasvir+ dasabuvir
• *Potential Tx candidates includes all those who are
expected to deteriorate within 3-5 years
Future (imminent) perspectives
Transplant recipients with recurrent HCV infection
• The ultimate goal would be to treat all potential
transplant recipients with recurrent HCV infection,
regardless of their disease stage and HCV genotype,
with a third-generation all oral DAA combination
(whichever first available),
– SOF + Daclatasvir
– SOF + Simeprevir
– SOF + Ledipasvir