I NUOVI FARMACI PER L' EPATITE C NEI PAZIENTI
TALASSEMICI, ONCOEMATOLOGICI ED EMODIALIZZATI
Vito Di Marco
Gastroenterology & Hepatology
Di.Bi.M.I.S.
University of Palermo
Patients with chronic HCV disease and co-morbidities
Key points
 First point: What is the role of HCV infection in the clinical course
of primary disease?
 Second point: What is the benefit of HCV clearance ?
(The Sustained Virological Response)
 Third point: What are the therapeutic options for patients with HCV
chronic hepatitis?
• yesterday
• today
• tomorrow
Key points
 First point: What is the role of HCV in the clinical course of
Thalassemia Major?
• severity of liver disease
• complications of disease and survival
 Second point: What is the benefit of HCV clearance ?
(The Sustained Virological Response)
 Third point: What are the therapeutic options for
thalassemia patients with HCV chronic hepatitis?
• yesterday
• today
• tomorrow
Liver disease in chelated transfusion-dependent thalassemics:
the role of iron overload and chronic hepatitis C.
V. Di Marco, M. Capra et al. Haematologica, 2008
Key points
 First point: What is the role of HCV in the clinical course of
Thalassemia Major?
• severity of liver disease
• complications of disease and survival
 Second point: What is the benefit of HCV clearance ?
(The Sustained Virological Response)
 Third point: What are the therapeutic options for
thalassemia patients with HCV chronic hepatitis?
• yesterday
• today
• tomorrow
Baseline features of 376 thalassemia patients
according to HCV status in 1993
HCV-RNA negative
189 pts (50.2%)
HCV-RNA positive
187pts (49.8%)
Age (years, mean, SD)
16 ± 9.3
20 ± 7.1
Gender ( males, %)
89 (47%)
96 (51%)
147
42
67
120
1,501
(288 – 9,720)
1,361
(133 – 8,240)
11
13
14
19
Serum ALT
• normal values
• upper normal limit
Serum Ferritin (ng/mL, median, range)
Diabetes
Cardiac disease
28 Patients (7%) were drop-out
(V. Di Marco, L. Cuccia , A. Maggio, M. Rizzo, C. Gerardi et al, 2014
HCV chronic infection and liver decompensation or HCC
p < 0.001
(V. Di Marco, F. Bronte, L. Cuccia , A. Maggio, C. Gerardi et al, 2014
HCV chronic infection and heart failure
p = 0.0012
(V. Di Marco, F. Bronte, L. Cuccia , A. Maggio, C. Gerardi et al, 2014
HCV chronic infection and overall survival
p < 0.001
(V. Di Marco, F. Bronte, L. Cuccia , A. Maggio, C. Gerardi et al, 2014
Key points
 First point: What is the role of HCV in the clinical course of
Thalassemia Major?
• severity of liver disease
• complications of disease and survival
 Second point: What is the benefit of HCV clearance ?
(The Sustained Virological Response)
 Third point: What are the therapeutic options for
thalassemia patients with HCV chronic hepatitis?
• yesterday
• today
• tomorrow
Biomarkers, surrogate end-points and true clinical end-points
Antiviral Tx
Disease
Stage
HCV-RNA
clearance
Death
Liver Transplant
Intermediate end-points
1. Liver Decompensation
2. Heart Decompensation
The biomarker is a solid end-point if:
1. It lies in a causal pathway of the disease process
2. It is modified by the intervention,
3. The modification of biomaker influence the clinical course of the disease
Alfa 2b-interferon monotherapy in thalassemic patients with
chronic C hepatitis.
Authors
Cuntries
N. of
patients
Mean
age
Pts with
cirrhosis
IFN dose
Months of
therapy
Rate of
SVR(*)
Clemente
(1994)
Italy
51
14
0%
3 MU/mq
t.i.w.
15
37%
Di Marco
(1997)
Italy
70
14
15%
3 MU/mq
t.i.w.
12
40%
Spiliopoulou
(1999)
Grecee
13
14
7.5%
3 MU
t.i.w.
18
75%
Sievert
(2002)
Australia
28
26
3.5%
3 MU
t.i.w.
6
28%
(*) SVR: sustained virological response:
V. Di Marco et al. Blood, 1997
Viral genotypes and Sustained Virological Response (SVR)
to alpha Interferon in Thalassemia Major patients
100
Therapy: alpha IFN 3 MU/mq for 48 weeks
SVR
90
80
NR
71.6%
70
(p < 0.001)
60
66.%
50
33.3%
40
30
28.4 %
20
10
0
Genotypes 1 & 4
Genotypes 2 & 3
(n= 109)
(n= 30)
V. Di Marco et al, Gastroenterology 2007
IL28B status and SVR in 114 thalassemia major patients
receiving IFN monotherapy.
V. Di Marco et al. Haematologica 2012;97 679-686
Disease events in 141 thalassemics with chronic C hepatitis
treated with IFN monotherapy
Liver Event
Incidence of Liver Disease Complication %
20
55 patients (39%) with Sustained virological Response
86 patients (61%) without Sustained Virological Response
18
16
14
12%
12
Log Rank (Mantel Cox): p = 0.012
SVR
10
0
1
8
6
4
0%
2
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Follow-up (years)
Number at risk
Group: 0
86 86
Group: 1
55 55
85
85
85
83
82
80
57
52
52
51
49
47
44
42
39
39
55
55
54
53
53
53
53
52
52
52
49
48
48
47
45
45
(V. Di Marco, Z. Borsellino, A. Maggio, C. Gerardi et al,)
Survival in 141 thalassemics with chronic C hepatitis
treated with IFN monotherapy
Mortality
100
98
96
94
92
90
88
86
84
82
80
78
76
96%
SVR
0
1
Log Rank (Mantel Cox): p = 0.007
1
2
3
4
5
6
78%
7 8 9 10 11 12 13 14 15 16 17
Follow-up(years)
Number at risk
Group: 0
86 86 85 85 84 82 57 55 48 46 45 44 41 38 34 31 31
Group: 1
55 55 55 55 55 53 52 52 51 51 51 48 47 46 45 42 42
(V. Di Marco, Z. Borsellino, A. Maggio, C. Gerardi et al,)
Key points
 First point: What is the role of HCV in the clinical course of
Thalassemia Major?
• severity of liver disease
• complications of disease and survival
 Second point: What is the benefit of HCV clearance ?
(The Sustained Virological Response)
 Third point: What are the therapeutic options for
thalassemia patients with HCV chronic hepatitis?
• yesterday
• today
• tomorrow
Baseline features of 230 Thalassemia patients with chronic hepatitis C treated
with PEG-IFN and RBV
Genotype 1
136 pts (59.1%)
Genotype 2
74 pts (32.2%)
Genotype 3
8 pts (3.5%)
Genotype 4
12 pts (5.2%)
Age (years, mean, SD)
36.5 ± 5.9
35.8 ± 6.0
34.9 ± 6.1
32.8± 7.0
Gender ( males, %)
77 (56.6%)
35 (47.3%)
6 (75%)
8 (66.6%)
Diagnosis :
Chronic Hepatitis
Cirrhosis
106 (78%)
30 (22%)
61 (82.4%)
13 (17.6%)
6 (75%)
2 (25%)
10 (83.3%)
2 (16.7%)
Serum ALT (IU/L, mean, range)
79 (16 -351)
65 ( 14-750)
114 (30-307)
100 (23-514)
Serum Ferritin (ng/mL, mean, range)
919
(19 - 7,000)
1,350,837
(1,28017,700,000)
899
(117-4,470)
1,391,913
(2,2908,193,000)
1225
(200-3471)
808
(260-610)
836,862
(85,034-2,148,00)
785,163
(2908-6,700,000)
Serum HCV-RNA levels
< 400,000 IU/L
> 400,000 IU/mL
64 (39.7%)
72 (60.3%)
28 (37.8%)
46 (62.2%)
3 (37.5%)
5 (62.5%)
7 (70%)
3 (30%)
IL 28B (169 patients):
CC
CT/TT
29 (26.8%)
79 (73.2%)
20 (40%)
30 (60%)
1 (25%)
3 (75%)
4 (50%)
3 (50%)
Treatment status:
Naive to antiviral treatment
Previuos IFN treatment
72 (52.9%)
64 (47.1%)
61 (82.4%)
13 (17.6%)
3 (37.5%)
5 (62.5%)
10 (83.3%)
2 (16.7%)
Serum HCV-RNA (IU/L, mean, range)
V. Di Marco et al, manuscript in progress
Kinetic of virological response according with viral genotypes
(Intention to treat analysis)
90%
SVR
EVR
RVR
88%
75%
67%
Patients (%)
57%
62%
62%
42%
37%
33%
22%
V. Di Marco et al, manuscript in progress
Kinetic of virological response in 108 genotype 1 patients
(Intention to treat analysis)
RVR
SVR
ETR
90%
81%
81%
72%
Patients (%)
66%
55%
49%
43%
38%
23%
14%
11%
V. Di Marco et al, manuscript in progress
SVR according with viral genotypes and RVR
(Intention to treat analysis)
RVR
NO RVR
86%
Patients with SVR
(%)
78%
75%
60%
34%
29%
25%
0%
n. patients
V. Di Marco et al, manuscript in progress
Blood transfusion during therapy
Increase of blood transfusion
during therapy (%)
28%
25%
10%
24
13%
12%
28
66
56
32
12%
24
n. patients
V. Di Marco et al, manuscript in progress
Key points
 First point: What is the role of HCV in the clinical course of
Thalassemia Major?
• severity of liver disease
• complications of disease and survival
 Second point: What is the benefit of HCV clearance ?
(The Sustained Virological Response)
 Third point: What are the therapeutic options for
thalassemia patients with HCV chronic hepatitis?
• yesterday
• today
• tomorrow
12 weeks of Sofosbuvir + Peg-IFN + Ribavirin
in naïve patients with chronic HCV hepatitis
(genotypes 1 and 4)
SVR12 According to
Fibrosis Level
SVR12 According to
Genotype
100
89
96
100
100
SVR12 (%)
SVR12 (%)
80
80
80
60
40
20
60
40
20
n/N = 261/292
0
92
GT 1
27/28
GT 4
Lawitz E, et al. N Engl J Med. 2013;369:678-9.
252/273
7/7
GT 5,6
0
No
Cirrhosis
43/54
Cirrhosis
Sofosbuvir + Ribavirin in patients with chronic HCV
hepatitis infected by genotype 2 or 3
Patient
Population
Genotype 2
Genotype 3
N
SVR12
Overall
N
Cirrhosis
SVR12
Cirrhosis
Rx Naive
70
97%
11
91%
Rx Limited
109
92%
17
94%
12 weeks
36
88%
10
60%
16 weeks
32
94%
9
78%
Rx Naive
183
56%
38
34%
Rx Limited
98
68%
14
32%
12 weeks
64
30%
26
19%
16 weeks
63
62%
23
61%
Treatment
Experienced:
Treatment
Experienced:
Sofosbuvir + peg-IFN + Ribavirin for 12 weeks in experienced
genotype 2 or genotype 3 patients.
Sofosbuvir 400mg + PEG-IFN + ribavirin 1000–1200 mg for 12 weeks,
96
83
100
93
9/9
13/14
83
83
SVR12 (%)
SVR12 (%)
89
42/47
26
22/23
20/24
Lawitz E, et al. AASLD 2013, Washington DC. #LB-4
10/12 10/12
No cirrhosis
Cirrhosis
Indipendent Study: Efficacy and tolerability of Sofosbivir associated with
Ribavirin (± Peg-Interferon) in thalassemia patients with chronic hepatitis C
Coordinator: Prof. Vito Di Marco, Palermo, Italy
Primary Endpoint: The Sustained Virological Response (SVR), defined as the absence of
HCV-RNA in serum by a highly sensitive test at the end of treatment and 6 months later.
Secondary Endpoints(s): The increase in the number of blood transfusions required to
maintain hemoglobin above 9 g/dL during the therapy
Group 1: Patients with HCV Genotype 1 infection
Duration of therapy: 12 weeks
Drugs: Sofosbuvir, 400 mg orally/daily plus Ribavirin, 1000-1200 mg orally/ daily plus alfa-2a
Peg-IFN,180 μg subcutaneously/ weekly
Group 2: Patients with HCV Genotype 2 Infection
Duration of therapy: 12 weeks
Drugs: Sofosbuvir, 400 mg orally/ daily plus Ribavirin, 1000-1200 mg orally/ daily
Group 3: Patients with HCV Genotype 3 Infection
Duration of therapy: 12 weeks
Drugs: Sofosbuvir, 400 mg orally/ daily plus Ribavirin, 1000-1200 mg orally/ daily plus alfa-2a
Peg-IFN, 180 μg subcutaneously/weekly
Group 4: Patients with HCV Genotype 1 or 3 unable to take IFN
Duration of therapy: 24 weeks
Drugs: Sofosbuvir, 400 mg orally/ daily plus Ribavirin, 1000-1200 mg orally/ daily
Centers
Center
Principal Investigator
U.O.C. di Gastroenterologia e Epatologia , Prof Vito Di Marco
Azienda Ospedaliera Universitaria “Paolo e-mail: [email protected]
Giaccone” Palermo
U.O.C. di Gastroenterologia ed
Epatologia, Fondazione IRCCS Cà
Granda Ospedale Maggiore Milano,
Dr.ssa Roberta D’Ambrosio
e-mail: [email protected]
U.O.C. di Gastroenterologia, Azienda
Ospedaliero Universitaria San Luigi
Gonzaga, Orbassano, Torino.
Prof Giorgio Maria Saracco
e-mail: [email protected]
U.O.S. "Diagnosi e Terapia delle
Epatopatie" e Ambulatorio Trapianto di
Fegato, IRCCS Azienda Universitaria
Ospedaliera, San Martino-IST, Genova,
Prof. Antonino Picciotto
e-mail: [email protected]
U.O.S.C. di Epatologia, Azienda
Ospedaliera di Rilievo Nazionale "A.
Cardarelli", Napoli
Dr Alfonso Galeota Lanza
e-mail: [email protected]
Key points
 First point: What is the role of HCV in the clinical course of
Thalassemia Major?
• severity of liver disease
• complications of disease and survival
 Second point: What is the benefit of HCV clearance ?
(The Sustained Virological Response)
 Third point: What are the therapeutic options for
thalassemia patients with HCV chronic hepatitis?
• yesterday
• today
• tomorrow
A Phase III Double Blind Clinical Trial to Study the Efficacy and Safety of the
Combination Regimen of MK-5172 and MK-8742 in Treatment-Naïve Subjects
with Chronic HCV GT1, GT4, GT5, and GT6 Infection with Inherited Blood
Disorders with and without HIV Co-Infection
MK-5172 (Gazaprovir): inhibitor of viral protease, NS3/4A, with pangenotypic activity
MK-8742 (Elbasvir): inhibitor of HCV non-structural protein, 5A (NS5A)
Phase 2 studies:
• A total of 899 patients with HCV have received MK-5172 for up to 18 weeks in
combinations with PR (PN003 and PN038), in combination with RBV alone
(PN039 and PN047), or in combination with MK-8742 +/-RBV (PN035 and
PN047).
• The patients included were GT 1, 2, 4, 5 or 6, non cirrhotic or cirrhotic, prior
PR treatment failures, or HIV co-infected.
• The dose range studied has been 25 mg – 800 mg QD.
• SVR: > 90%
The Study include:
HCV Patients with Sickle Cell (SS) Anemia, n=88
HCV Patients with βThalassemia, n=88
HCV Patients with Hemophilia A or B, n=19
Arm 1:
Immediate Treatment: Galzaprovir 100 mg plus Elbasvir 50mg for 12 weeks + 24
weeks of follow-up
Arm 2:
Deferred Treatment: Placebo for 12 weeks + 4 weeks of follow-up, then open label
treatment Galzaprovir 100 mg plus Elbasvir 50mg for 12 weeks + 24 weeks of
follow-up
Hepatitis C-associated B-cell non-Hodgkin lymphomas.
 B-NHL subtypes most frequently associated with HCV:
 marginal zone lymphoma
 diffuse large B-cell lymphoma.
 Three theories:
1. continuous external stimulation of lymphocyte receptors by viral antigens and
consecutive proliferation;
2. HCV replication in B cells with oncogenic effect mediated by intracellular viral proteins;
3. permanent B-cell damage, e.g., mutation of tumor suppressor genes, caused by a
transiently intracellular virus (‘‘hit and run’’ theory).
J Peveling-Oberhag, Journal Hep 2013; 59:169–177
Chronic HCV infection and lymphoproliferative disorders:
mixed cryoglobulinemia syndrome, MGUS and B-cell non-Hodgkin lymphoma
G. Caviglia, J Gastroenterol Hepatol. 2014 Oct 28
Chronic HCV infection and lymphoproliferative disorders:
mixed cryoglobulinemia syndrome, MGUS and B-cell non-Hodgkin lymphoma
Cirrhosis is an additional risk factor for the development of lymphoproliferative
disorders in patients with chronic HCV infection.
G. Caviglia, J Gastroenterol Hepatol. 2014 Oct 28
Clinical outcome of hepatitis C virus-positive diffuse large Bcell lymphoma patients according to retrospective studies
C. Visco World J Gastroenterol 2014 ; 20: 11054-11061
Antiviral therapy is associated with a better survival in patients
with hepatitis C virus and B-cell non-Hodgkin lymphomas
(ANRS HC-13 lympho-C study)
Multicentric study: 116 HCV-positive patients with B-NHL
between 2006 and 2012.
 45 (39%) marginal zone lymphoma (MZL)
 45 (39%) diffuse large B-cell lymphoma (DLBCL)
 26 (22%) other types
Among 55 patients receiving AT, a SVR was achieved in
 23 of 38 (61%) patients with MZL
 9 of 17 (53%) with DLBCL .
J-M Michot. American Journal of Hematology, 2014
Antiviral therapy is associated with a better survival in patients
with hepatitis C virus and B-cell non-Hodgkin lymphomas
(ANRS HC-13 lympho-C study)
Outcomes of HCV-associated B-NHL
according to the cytohistological
Groups.
J-M Michot. American Journal of Hematology, 2014
Antiviral therapy is associated with a better survival in patients
with hepatitis C virus and B-cell non-Hodgkin lymphomas
(ANRS HC-13 lympho-C study)
Outcomes of HCV-associated
B-NHL according to HCV antiviral
Treatment.
J-M Michot. American Journal of Hematology, 2014
Antiviral treatment in patients with indolent B-cell lymphomas associated with
HCV infection: a study of the Fondazione Italiana Linfomi.
Cohort study of 704 consecutive HIV-negative, HCV-positive patients with
indolent NHL diagnosed and treated from 1993 to 2009 in 39 centers of the
Fondazione Italiana Linfomi;
5-year overall survival (OS): 78% [95% CI: 74%-82%]
5-year progression-free survival (PFS): 48% (95% CI: 44%-53%).
Multivariate analysis, the use of AT during the patients' life had positive impact
on OS.
Forty-four of the 100 patients treated with first-line AT achieved a complete
remission (CR) and 33 a partial response (PR).
HCV-RNA clearance was achieved in 80 patients and was related to
lymphoma response.
At a median follow-up of 3.6 years, 5-year PFS was 63% (95% CI: 50%-73%).
CR + PR rate was 85% with AT as second-line treatment.
Arcaini L, Ann Oncol. 2014
Hepatitis C infection is very rarely treated among hemodialysis
patients.
 The Dialysis Outcomes and Practice Patterns Study:
• Observational study included 49,762 HD patients in 12 nations
(1996-2011).
• 4,735 patients (9.5%) were HCV+
• 48 (1.0%) of the 4,589 HCV+ patients with prescription data received
antiviral therapy.
• 617 HCV+ patients on a waiting list for renal transplantation, only
3.7% were receiving treatment.
 After restricting to HCV+ patients with overlapping propensity for antiviral
treatment, 4 (9.5%) of 42 treated patients and 638 (21.0%) of 3,037
untreated patients died.
 The hazard ratio for adjusted mortality comparing treated patients with
untreated patients was 0.47 (95% CI, 0.17-1.26).
Goodkin DA Am J Nephrol. 2013
Antiviral therapy (pegylated interferon and ribavirin) of hepatitis C in dialysis
patients: meta-analysis of clinical studies
Characteristics of clinical studies: demographic data
Characteristics of clinical studies and histologic and virological data
F. Fabrizi, Journal of Viral Hepatitis, 2014, 21, 681–689
Antiviral therapy (pegylated interferon and ribavirin) of hepatitis C in dialysis
patients: meta-analysis of clinical studies
F. Fabrizi, Journal of Viral Hepatitis, 2014, 21, 681–689
J Hepatol. 2013
Treatment of patients with co-morbidities
Haemodialysis patients.
Treatment of patients with co-morbidities
Haemoglobinopathies.
Who should be treated: EASL recommendations 2014
In principle, all patients with chronic HCV infection, but in
a situation of limited availability:
• F3-F4: Priority
Patients with NHL
Patients on dialysis
• F2: Reasonable
Thalassemia patients
• F0-F1: Debatable
Informed deferral of treatment for patients with mild disease
EASL Online Recommendations on Treatment of Hepatitis C, April 2014
What about the patient in your clinic today?