I portatori di epatite cronica e malattie correlate: una nuova

HCV: La realtà clinica
MALATTIE DI FEGATO
5° causa di morte al mondo
(dopo patologie cardio e cerebro-vascolari,
polmonari, oncologiche)
HBV
HCV
ETOH
AFLATOSSINA
NAFLD
WHO - UK NATIONAL STATISTICS
HCV:
Epidemiologia e distribuzione dei Genotipi
EASL update on hepatitis C, November 2014
EPIDEMIOLOGIA DELL’INFEZIONE DA HCV
TECHNICAL REPORT Hepatitis B and C in the EU
neighbourhood: prevalence, burden of disease and screening
policies September 2010
PREVALENZA HCV PER CLASSI DI ETÀ E
PROVENIENZA GEOGRAFICA
%
35
Sud
30
25
20
Centro
15
Nord
10
5
0
< 30
30-39
40-49
50-59
> 60
Maio R et al, J Hepatol 2000
Di Stefano G et al, J Med Virol 2002
HCV: GRADIENTE NORD-SUD
Prevalenza della positività di HCV-RNA nelle diverse regioni italiane in relazione all’età
Brescia Vallecamonica - Sebino
AISF –FIRE - Libro Bianco dell’Epatologia Italiana - EPIDEMIOLOGIA DELLE EPATOPATIE ACUTE E CRONICHE IN ITALIA.
A cura della Commissione “Epidemiologia” dell’Associazione Italiana per lo Studio del Fegato (A.I.S.F.) Febbraio 2007. - Zani et al DLD 2011.
HCV: PRINCIPALE CAUSA DI EPATOPATIA
CRONICA IN ITALIA
ALTRO
15,6%
HBsAg +
9,9%
AlCOL+HCV
12,1%
ALCOL
6,2%
HCV: 1.5-2 milioni di infetti in Italia
HCV +
56,6%
THE LIVER MATCH STUDY
Main Indications For Liver Transplantation in Italy
Total number of first liver transplants = 1240
50 % dei Trapianti in pazienti con infezione da HCV
Re-OLTx N. = 100 (7.5%)
* Autoimmune 0.35%; liver rupture 0.15%
Angelico et al. Dig Liv Dis; 2011, mod.
STORIA NATURALE HCV
10%
Infezione protettiva
Immunità T-cellulare
Infezione
5%
10%
75%
Infezione subclinica
ALT normali
Epatite acuta
Epatite cronica
15-25%
Guarigione
Cirrosi
1-4%
HCC
Scompenso
STORIA NATURALE HCV
Infezione
75%
Epatite cronica
5-30 anni
15-25%
Cirrosi
1-4%
HCC
>30%
Scompenso
PROGRESSIONE HCV: Ruolo Cofattori
FATTORI LEGATI
ALL’OSPITE
ALTRI FATTORI
Età avanzata
Sesso: M>F
Stato immunitario
Alcol
Farmaci
Steatosi
Coinfezioni HCV, HIV
FATTORI LEGATI AL
VIRUS
Carica virale
Genotipo
Più rapida progressione epatopatia HCV relata
Liaw, Liver Int 2006
PROGRESSIONE HCV
Picco di incidenza infezione HCV negli anni 50-70
prima che fossero disponibili test per HCV
La maggior parte dei pazienti con epatite cronica C si
trova attualmente nella 5°-7° decade di vita
Quando raggiungeranno 60-70 anni
probabile patologia clinicamente manifesta
Manifestazioni extraepatiche
dell’infezione da HCV
A: Association defined on the basis of:
1.
High prevalence
2.
Pathogenesis

Mixed cryoglobulinemia,
cryoglobulinemic nephropathies
B: Association defined on the basis of higher
prevalences than in controls

B-cell non-Hodgkin’s lymphoma

Monoclonal gammopathies

Porphyria cutanea tarda

Lichen planus
D: Anecdotal observations
C: Associations to be confirmed/characterized

Psoriasis, Vitiligo

Peripheral/central neuropathies

Autoimmune thyroiditis

Polyarthritis Rheumatoid arthritis

Thyroid cancer

Polyartheritis nodosa

Sicca syndrome

Bechet’s syndrome

Alveolitis-Lung fibrosis

Poly/dermatomyositis, Fibromyalgia

Diabetes mellitus

Chronic urticaria/pruritus

Non-cryoglobulinemic

Kaposi’s pseudo-sarcoma

nephropathies

Cardiopathies/cardiomyopathies

Mooren corneal ulcer

Erectile dysfunctions
CONSEGUENZE CLINICHE
 Attualmente l’infezione da HCV è responsabile di:
 12000-16000 decessi/anno negli USA
 8000-12000 decessi/anno in Italia
 Negli USA, sulla base di proiezioni epidemiologiche
si stima che, nelle prossime 2 decadi:
 aumento ospedalizzazioni per epatopatia HCVrelata di circa 25-30% per anno
 aumenterà di 2-4 volte della mortalità per HCV
McHutchinson JG et al, Am J Manag Care 2005
MORTALITÀ DA MALATTIA DI FEGATO
2010
morti/100.000
abitanti
60
Maschi
50
40
Femmine
30
20
10
0
15
25
35
45
55
età
65
75
85
95
PROIEZIONE DELLE PATOLOGIE EPATICHE
HCV-RELATE NEI PROSSIMI DECENNI
Epatite cronica HCV
Nei prossimi 40 anni il
numero totale di pazienti con
epatite cronica C diminuirà
gradualmente
prevalenza (x 1000)
3500
3000
2500
2000
1500
1000
500
0
2000
2010
2020
2030
2040
Il numero dei casi di cirrosi
crescerà più del 50% per il
2010
e
successivamente
subirà un plateau
prevalenza (x 1000)
Cirrosi HCV-relata
1000
900
800
700
600
500
400
300
200
100
0
In particolare, la percentuale
di epatiti croniche HCVrelate che evolverà in cirrosi
aumenterà del 25% nel 2010,
del 32% nel 2020, del 36%
nel 2030, del 38% nel 2040
2000
2010
2020
2030
2040
Davis GL et al. Liver Transpl, 2003
PROIEZIONE DELLE PATOLOGIE EPATICHE
HCV-RELATE NEI PROSSIMI DECENNI
prevalenza (x 1000)
Cirrosi HCV-relata scompensata
160
140
120
100
80
60
40
20
0
2000
2010
2020
2030
2040
Incremento
casi
scompenso epatico
HCC in pazienti HCV+
16
14
prevalenza (x 1000)
Parallelamente ad un
aumento progressivo dei
pazienti affetti da cirrosi
epatica si assisterà a:
Incremento
di HCC
12
10
8
di
comparsa
6
4
2
0
2000
2010
2020
2030
2040
Davis GL et al, Liver Transpl 2003
MORTALITÀ PER TUMORE AL FEGATO IN EUROPA CORRELATA
ALLA POSITIVITÀ PER MARCATORI HCV E HBV
TECHNICAL REPORT Hepatitis B and C in the EU neighbourhood:
prevalence, burden of disease and screening policies September 2010
HCV THERAPY
Boceprevir or
Telaprevir +
P/R
Interferon +
Ribavirin
Simeprevir or
Sofosbuvir +
P/R
2005
2011
2014
GT1
1991
1998
2001
GT2/3
Standard
Interferon
2014
Peginterferon/
Ribavirin
Sofosbuvir +
Ribavirin
dic. ’14
19
RISPOSTA ALLA TERAPIA ANTI-HCV
(fino al 2013)
RISPOSTA VIROLOGICA SOSTENUTA (SVR)
HCV 1
HCV 2/3
HCV 4
HCV 5
HCV 6-9
40-70%
75-85%
40-68%
58-71%
40-62%
Terapia basata su
interferone/ribavirina e nel G1 anche
su DAA di I generazione
HCV LIFE CYCLE AND NOVEL DAA TARGETS
NS5A inhibitors
Block replication complex formation, assembly
Receptor binding
and endocytosis
Translation and
polyprotein
processing
Transport
and release
Fusion
and
uncoating
ER lumen
(+) RNA
LD
LD
LD
NS3/4 protease
inhibitors
Membranous
web
ER lumen
Virion
assembly
NS5B polymerase
inhibitors
RNA
replication
Nucleoside/nucleotide
RNA replication
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Nonnucleoside
Key Negative Features of 1st generation
DAAs
Pill Burden
Low genetic barrier to resistance
Subpar efficacy in some patients
Poor Tolerability
Emergence of Pre-existing Resistant
Variants During Treatment with DAA
Drug Potency
HCV RNA
Baseline HCV RNA
Viral breakthrough
Resistance
Barrier
X
X X X
X X
X
X X
Before Treatment
Time on Treatment with DAA Alone
Resistant virus
Sensitive virus
SVR by Fibrosis Stage and Prior Response to Peg-IFN/RBV
100
Prior
relapsers
86%
Prior null
responders
85%
80
SVR (%)
Prior partial
responders
72%
60
42%
41%
40
25%
20
144/167
101/119
F0/F2
F3/F4
34/47
21/50
24/59
22/88
F3/F4
F0/F2
F3/F4
0
Zeuzem S, et al. NEJM 2011
F0/F2
CUPIC: SVR12 and the risk of occurrence of severe
complications
Albumin
<35 g/L
Albumin
≥35 g/L
N
Complications, n (%)
SVR12, n (%)
N
Complications, n (%)
SVR12, n (%)
Hézode C, et al. Gastroenterology. 2014 Jul;147(1):132-142
Platelets count
Platelets count
≤100,000/mm3
>100,000/mm3
37
31
19 (51.4%)
5 (16.1%)
8 (21.6%)
8 (29.0%)
74
306
9 (12.2%)
19 (6.2%)
25 (33.8%)
165 (53.9%)
Percentage of patients (%)
Anaemia & Rash Adverse Events: The Telaprevir EAP
Grade 1: Hb 10.0 – 10.9 g/dL; decrease 2.5 – 3.4 g/dL
Grade 2: Hb 9.0 – 9.9 g/dL; decrease 3.5 – 4.4 g/dL
Grade 3: Hb 7.0 – 8.9 g/dL; decrease >4.5 g/dL
Grade 4: Hb <7.0 g/dL
59%
Colombo M et al, Gut 2014; 63(7):1150-8
42%
2nd Generation DAAs
2nd Wave Protease inhibitors
Simeprevir (SMV)
NS5B Polymerase inhibitors
Sofosbuvir (SOF)
NS5A Inhibitors
Daclatasvir(DCV)
Key Features of 2nd generation DAAs
SMV
SOF
DCV
Pill Burden
+
+
+
Tolerability
+/-
+
+
Genetic barrier to
resistance
+/-
+
+/-
+
+
+
Efficacy in difficult to
cure patients
1. ABT 450 (with ritonavir: ABT 450r):
protease inhibitor
2. Ombitasvir (ABT 267): NS5A
inhibitor
3. Dasabuvir (ABT 333):
nonnucleoside polymerase
inhibitor
4. Sofosbuvir: nucleotide polymerase
inhibitor
5. Ledipasvir: NS5A inhibitor
6. Daclatasvir: protease inhibitor
7. Simeprevir: protease inhibitor
Single tablet
Coformulation
once daily
Twice daily
Single tablet
Coformulation
once daily
Gennaio/maggio 2014
1.
2.
3.
4.
5.
6.
Daclatasvir plus Sofosbuvir for HCV Infection
Treatment of HCV with ABT-450/r–Ombitasvir and Dasabuvir with
Ribavirin
ABT-450/r–Ombitasvir and Dasabuvir with Ribavirin for Hepatitis C
with Cirrhosis
Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection
Ledipasvir and Sofosbuvir for Previously Treated HCV Genotype 1
Infection
Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without
Cirrhosis
24 aprile 2014
SAPPHIRE-I (funded by Abbvie)
dic. ’14
31
SAPPHIRE-I
• Phase 3 trial
• Multicenter, Randomized, Double-blind, Placebocontrolled trial
• Previously untreated patients with HCV genotype 1
infection and no cirrhosis
• Interferon-free regimen, all oral antiviral therapy
dic. ’14
32
SAPPHIRE-I: results
dic. ’14
33
“Virologic Failure With
3 DAAs + RBV in Treatment-Naive Pts”
SAPPHIRE-I
• Virologic failure occurred in 7 patients with GT1a and 1 patient with GT1b
• Relapses occurred at posttreatment Wk 2 (n = 3), Wk 8 (n = 3), and Wk 12 (n = 1)
• Emergent resistance-associated variants uncommon: 8/473 pts (1.7%)
– GT1a: D168V (6/7) in NS3; M28T (2/7) and Q30R (3/7) in NS5A; and S556G (3/7) in NS5B
– GT1b: Y56H + D168V in NS3; L31M + Y93H in NS5A; and S556G in NS5B
dic. ’14
34
ADVERSE EVENTS
SAPPHIRE-I
dic. ’14
35
11 aprile 2014
TURQUOISE II (sponsored by Abbvie)
dic. ’14
36
TURQUOISE II
• Open-label
• Phase 3 trial
• Involving Inclusion criteria:
 GT1
 Compensated cirrhosis (Child-Pugh A)
 DAA naïve (previously untreated and previously treated)
 HCV RNA level of more than 10,000 IU per milliliter
 Radiographic ascites and varices permitted, serum albumin ≥ 2.8
g/dL, total bilirubin < 3 mg/dL, serum AFP ≤ 100 ng/mL, INR ≤ 2.3,
platelets ≥ 60,000 cells/mL
dic. ’14
37
TURQUOISE II: results
Sustained Virologic Response at Post-Treatment Week 12 in Each Treatment Group, Overall and According to
Subgroups
dic. ’14
38
TURQUOISE II: results
GT1a
SVR12 (%)
100
100 100
92.9
80.0
12 wks
24 wks 100
80
80
60
60
40
40
20
20
0

92.2 92.9
93.3100
59/ 52/
64 56
Naive
14/ 13/
15 13
11/ 10/
11 10
40/ 39/
50 42
Relapse Partial
Null
Response Response
0
GT1b
100 100
100 100
85.7100
100 100
22/ 18/
22 18
25/ 20/
25 20
6/7 3/3
14/ 10/
14 10
Naive
Relapse Partial
Null
Response Response
Virologic failure in 17/380 pts (4.5%); relapse more frequent with 12-wk vs 24-wk treatment (12 vs
1 pt), 7/12 relapsers by posttreatment Wk 12 were GT1a null responders
Poordad F, et al. EASL 2014. Abstract O163. Reproduced with permission.
dic. ’14
39
TURQUOISE II: adverse events
Titolo della Presentazione
dic. ’14
40
15 maggio 2014
Afdhal N et al
ION-1: sponsored by Gilead
dic. ’14
41
ION-1
• Phase 3
• Multicenter, Randomized, Open-label study
• Previously untreated patients with chronic HCV genotype
1 infection
• No upper limits for age or body-mass index
• Patients with cirrhosis could account for approximately
20% of the study population
dic. ’14
42
ION-1: results
100
99
94
97
100
98
94
99
100
SVR12 (%)
80
No cirrhosis
60
Cirrhosis
40
20
0
179/
180
32/
34
SOF/LDV
178/
184
SOF/LDV + RBV
12 Wks
•
•
•
33/
33
181/
184
31/
33
SOF/LDV
179/
181
36/
36
SOF/LDV + RBV
24 Wks
SVR12 rates did not differ by GT1a vs GT1b in any treatment arm
Virologic failure: 1 breakthrough in 24-wk SOF/LDV; 2 relapses (1 in 12-wk SOF/LDV, 1 in 24-wk SOF/LDV)
16% of patients had NS5A resistance-associated variants at baseline; 96% of these achieved SVR12
Mangia A, et al. EASL 2014. Abstract O164. Reproduced with permission. Afdhal N, et al. N Engl J Med. 2014;[Epub ahead of print].
dic. ’14
43
ION-1
17 aprile 2014
Afdhal N et al
ION-2: sponsored by Gilead
dic. ’14
45
ION-2
• Phase 3
• Randomized, Open-label study
• Patients infected with HCV genotype 1 who had not had a sustained
virologic response after treatment with peginterferon and ribavirin,
with or without a protease inhibitor (NS3/4A protease inhibitor)
(experienced)
• Patients who had discontinued prior treatment owing to an adverse
event were not eligible
• 20% of participants had cirrhosis, 41% to 46% were previous
nonresponders, and 46% to 61% had failed a PI
dic. ’14
46
ION-2
100
93
96
94
97
100
98
98
100
SVR12 (%)
80
Failure on
pegIFN/RBV
Failure on PI
60
40
20
0
40/
43
62/
66
LDV/SOF
45/
47
LDV/SOF + RBV
12 Wks
•
•
62/
64
58/
58
49/
50
LDV/SOF
58/
59
51/
51
LDV/SOF + RBV
24 Wks
Virologic failure: 1 breakthrough in 24-wk SOF/LDV/RBV due to nonadherence; 11 relapses (7 in 12wk SOF/LDV, 4 in 12-wk SOF/LDV/RBV)
14% of patients had NS5A resistance-associated variants at baseline; 89% of these achieved SVR12
Afdhal N, et al. EASL 2014. Abstract O109. Reproduced with permission. Afdhal N, et al. N Engl. J Med. 2014;370:1483-1493.
dic. ’14
47
ION-2
Titolo della Presentazione
dic. ’14
48
15 magio 2014
Kowdley KV et al
ION-3
dic. ’14
49
ION-3
• Multicenter, Randomized, open-label trial
• Phase 3
• 18 years of age or older
• Chronic HCV genotype 1 infection without cirrhosis
• Naïve to treatment for HCV infection
• HCV RNA level of at least 104 IU per milliliter at the time of screening, alanine
and aspartate aminotransferase levels of no more than 10 times the upper
limit of the normal range, a platelet count of more than 90,000 per cubic
millimeter, and a hemoglobin level of at least 11 g per deciliter (in women) or
at least 12 g per deciliter (in men).
dic. ’14
50
ION-3
Wk 8
Wk 12
SOF/LDV (n = 215)
Treatment-naive,
noncirrhotic pts with
HCV GT1
(N = 647)
SOF/LDV + RBV (n = 216)
SOF/LDV (n = 216)
Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200
mg/day
Patients were randomly assigned in a 1:1:1 ratio
Randomization was stratified according to HCV genotype (1a or 1b)
dic. ’14
51
ION-3
P = .52
P = .30
P = .70
100
94
93
95
SVR12 (%)
80
60
40
20
0
202/215
SOF/LDV
8 Wks
•
•
201/216
206/216
SOF/LDV + RBV
SOF/LDV
12 Wks
SVR12 rates did not differ by GT1a vs GT1b in any treatment arm
Virologic failure: 23 relapses (11 in 8-wk SOF/LDV, 9 in 8-wk SOF/LDV/RBV, 3 in 12-wk SOF/LDV)
ION-3
Pretransplant Sofosbuvir + Ribavirin
•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
- Amendment: extend treatment duration to 48 weeks or LT
Curry MP et al, Gastroenterology in press
Results: Post-Transplant Virologic Response
*3 subjects were >LLOQ at transplant.
†1 subject has not reached pTVR12, 1 subject LTFU at Week 8 post transplant.
Curry MP et al, Gastroenterology in press
SVR and The Natural History of Hepatitis C
Variceal Bleeding
Acute Hepatitis
Chronic Hepatitis
Cirrhosis
Liver decompensation
HCC
Modified by Lauer and Walker NEJM 2001;345:41-52
SVR and The Natural History of Hepatitis C
HCC
Unproved and Unprovable with IFN!
IFN contraindicated in decompensated cirrhosis
Acute Hepatitis
Chronic Hepatitis
Cirrhosis
Liver decompensation
and after variceal bleeding
Low SVR rates in patients with HCC
Variceal Bleeding
Modified by Lauer and Walker NEJM 2001;345:41-52
SOF+RBV for Treatment of Chronic HCV with Cirrhosis
and Portal HTN ± Decompensation: Week 24 Interim Results
Randomized, open-label, safety and efficacy study of SOF+RBV for 48 weeks compared to observation
for 6 months in patients with HCV cirrhosis and portal HTN (CTP 5–9)
Wk
24
Wk 0
Wk
48
Wk
72
Wk
96
SOF + RBV
n=25
Observation
n=25
18 (72)
20 (80)
56 (43‒69)
55 (44‒69)
8 (32)
7 (28)
6.1 (4.4‒7.0)
6.1 (3.8‒6.9)
1a
10 (40)
9 (36)
1b
9 (36)
6 (24)
2
2 (8)
1 (4)
3
2 (8)
8 (32)
4
2 (8)
1 (4)
IL28B non-CC, n (%)
22 (88)
18 (72)
Prior HCV treatment, n (%)
17 (68)
23 (92)
16.9 (9‒29)
16.2 (7‒27)
19 (76)
20 (80)
Male, n (%)
Median age, y (range)
Arm 1
n=25
SOF 400 mg + RBV 1000‒1200
mg
BMI ≥30
SVR12
Observation
SOF 400 mg + RBV 1000‒1200
mg
Preliminary
results
n (%)
Mean HCV RNA, log10 IU/mL
(range)
SVR12
Arm 2
n=25
kg/m2,
GT, n (%)
Mean HVPG mmHg, n (range)
HVPG >12 mmHg, n (%)
Afdhal N, EASL, 2014, O68
Difficult-to-Treat Patients:
Decompensated Cirrhosis and Portal Hypertension
Afdhal N et al, EASL OC #68
Difficult-to-Treat Patients:
Decompensated Cirrhosis and Portal Hypertension (II)
MELD Changes During Treatment/Observation
Afdhal N et al, EASL OC #68
The Risk of Treating Patients with Too Advanced
Liver Disease
Pellicelli A et al, Digestive and Liver Disease 2014; 46: 923-927
EPATITE HCV: CONCLUSIONI
Le malattie epatiche croniche rappresentano un serio
problema medico e sociale
L’infezione da virus HCV è un grande problema
sanitario specie nei paesi in via di sviluppo
L’epatopatia conseguente all’infezione e’ un problema
che colpisce il 2-7% della popolazione italiana
In conseguenza dell’effetto coorte di HCV, le previsioni
relative ai prossimi 40 anni identificano nella
popolazione geriatrica la massima prevalenza di
epatopatici cronici
EPATITE HCV: CONCLUSIONI
Nell’anziano la probabilità che si verifichi un evento in grado
di determinare uno scompenso epatico è maggiore rispetto al
giovane
Dopo il primo di questi eventi la sopravvivenza si riduce
drasticamente
Prevenzione complicanze
Studi efficacia/tollerabilità
Stretto follow-up
terapia antivirale negli anziani
Criteri di inserimento in lista
OLT meno restrittivi
EPATITE HCV: CONCLUSIONI
L’efficacia delle nuove terapie antivirali per il virus C
cambiera’ l’approccio clinico e la tipologia di pazienti
trattabili
Costi
Willingness to pay
Futilita’
Treatment Options
PegIFNa + ribavirin + sofosbuvir
12 weeks
PegIFNa + ribavirin + simeprevir
12 weeks
+RGT 12/36
PegIFNa + ribavirin + daclatasvir
12 weeks
+RGT 12
Sofosbuvir + ribavirin
12-24 weeks
Sofosbuvir + simeprevir (± ribavirin)
12 weeks
Sofosbuvir + daclatasvir (± ribavirin)
12-24 weeks
The (Probable) Italian Scenario
2nd Generation DAAs available in 2015 for:
Liver Transplant Patients
Patients on the OLT waiting list
Decompensated Patients
Patients with cirrhosis
INFEZIONE CRONICA VIRALE: SCENARIO ATTUALE
HCV
HBV
HIV
600.000
140.000
DECESSI / ANNO
230.000
> 11.000
100.000
1.500
22.000
937
INSERITA in PSN
NO
NO
SI
LEGGE AD HOC CON
FINANZIAMENTI
NO
NO
SI
NUMERO VERDE
NO
NO
SI
CAMPAGNE DI
SENSIBILIZZAZIONE
NO
NO
SI
STIME PORTATORI VIRUS ≈1.600.000
STIME CIRROSI / AIDS
Dati ISS