Transcript Slide 1

Treatment of Chronic
Hepatitis C in HCV-HIV
Infected Patients
J Mallolas
Infectious Diseases Service
Hospital Clínic
Barcelona
1. Why
to treat
HCV in HIV patients ?
Why to treat HCV in HIV patients ?
1. Longer survival
2. Faster progression to cirrhosis
3. Higher mortality due to ESLD
4. Higher risk of antiretroviral
hepatotoxicity
5. Faster progression of HIV disease
Incidence of Mortality in HIV-Infected Patients at the
Hosp. Clinic (Barcelona, Spain) between 1984-1998
Incidence of Mortality in HIV-Infected Patients at the
Hosp. Clinic (Barcelona, Spain) between 1984 - 1998
NO. x100 EXPOSED PATIENTS
xYEAR
40
No Tx
1NRTI
2NRTI
HAART
30
20
10
0
82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98
YEAR
HAART: Highly Active Antiretroviral Therapy (2NRTI plus 1PI/NNRTI)
HAART: Highly Actibe Antiretroviral Therapy ( 2NRTI plus 1PI/NNRTI)
Effect of HIV on HCV Liver Fibrosis
Progression Rate
Fibrosis Grades
(METAVIR Score)
4
3
2
HIV+ (n = 122)
1
Matched controls (n = 122)
Simulated controls (n = 122)
0
0
10
20
30
Duration of HCV Infection (years)
Increase with CD4 <200/mm3, ETOH, age
Benhamou et al. Hepatology 1999;30:1054.
40
Causes of death per year in HIV patients
Hospital Clínic. Barcelona
100%
90%
80%
70%
Cardiovascular causes
Accidental causes
Neoplasias
End-stage liver disease
AIDS-related illnesses
60%
50%
40%
30%
20%
10%
0%
1997
1998
1999
2000
2001
Risk factors of Hepatotoxicity in HCVHIVcoinfected patients:
Author
No.
ART
Rodriguez1
132
PI-based
Sulkowski2
211
Saves3
HCV
CD4
Rate
Predictors
62%
324
11%
HCV Alc.
PI-based
51%
109
12%
HCV CD4
1249
2 NRTIs
44%
234
6%
HCV HBV
den Brinker4
394
PI-based
22%
150
18%
HCV HBV
Martínez5
610
NVP-based
51%
279
9.7%
HCV ALT
Núñez6
222
ART
40%
337
9%
HCV age, Alc.
1. Rodriguez-Rosado et al. AIDS 1998;12:1256. 2. Sulkowski et al. JAMA
2000;283:74. 3. Saves et al. AIDS 1999;13:F115. 4. den Brinker et al. AIDS
2000;14:2895. 5. Martínez et al. AIDS 2001;15:1261. 6. Núñez et al. J AIDS
2001;27:426.
2. How to treat HCV
in HIV patients ?
Sustained Response to HCV Therapy
HIV-neg
HIV-pos
IFN monotherapy
20%
10%
IFN + ribavirin
45%
20%
Peg-IFN + ribavirin
55%
?
Peginterferon alfa-2b plus
ribavirin compared with
interferon alfa-2b plus
ribavirin for treatment of
HIV/HCV co-infected
patients
AIDS 2004, 18:F27–F36
Methods
• Randomized, single-centre, open-label clinical trial
including patients with:
• HCV:
– detectable HCV-RNA,
– alanine aminotransferase >1.5-fold upper limit of normal
– abnormal liver histology
• HIV:
– CD4 cell count >250 x106 cell/L
– HIV- RNA , <10,000 copies/ml
AIDS 2004, 18:F27–F36
Response by Treatment Group, ITT
PEG + RBV (n=52)
IFN + RBV (n=43)
100
P=0.033
P=0.017
% of patients
80
60
52
44
40
30
21
20
0
VR
AIDS 2004, 18:F27–F36
SVR
Response by Genotype 1-4, ITT
PEG + RBV (n=52)
IFN + RBV (n=43)
100
P=0.011
% of patients
80
P=0.007
60
41
38
40
20
11
7
0
VR
AIDS 2004, 18:F27–F36
SVR
Response by Genotype 2-3, ITT
PEG + RBV (n=19)
100
IFN + RBV (n=15)
P=0.914
P=0.730
% of patients
80
68
67
53
60
47
40
20
0
VR
AIDS 2004, 18:F27–F36
SVR
fl u
-li
2= ke
as Sd
3= the n
a
4= n o ia
de rex
pr
i
es a
6= 5= si
ga al on
str ope
oi
nt cia
es
7= t ina
ce l
8= fal
m ea
ial
9 g
10 =a ias
n
11 =l e em
=p uco ia
laq pe
ue nia
t
13 12 o pe
n
= =i r
14
re rita ia
=
a
b
hy ctio ili ty
pe n
rl a l oc
15 ct at a l
e
=
ins mia
om
16 nia
=
ot
he
r
1=
% of patients
Side effects (I)
• 92% of patients developed adverse events.
100
80
60
40
20
0
Adverse Events
Side effects (II)
• Premature discontinuation: 19% (Peg 23 vs 14%); 15% due to side
effects (17 vs 12%)
Premature
cumulative
discontinuation%
20
15
10
PEG+RBV
INF+RBV
5
0
2
4
8
12
16
40
– Severity of the adverse events not shown differences between two
arms.
PEG+RBV
INF+RBV
TOTAL
p-value
Grade 1-2
290 (84%)
189 (85%)
479 (84,4%)
NS
Grade 3-4
56 (16%)
33 (15%)
89 (15.6%)
NS
Conclusions
• PEG-INF  2b + RBV was significantly more
effective than IFN  2b + RBV for the treatment
of chronic hepatitis C in HIV co-infected patients,
mainly of genotype 1 or 4.
• Side effects were very frequent, the majority of
them were mild or moderate.
• Total CD4 fell in both arms but no evidence of
deleterius effect on HIV control were seen.
AIDS 2004, 18:F27–F36
Superiority of Peg IFN-Ribavirin
(Sustained Virological Response)
IFN type
n.
IFN/RBV
PEG IFN/RBV
ACTG
2a
133
12%
27%
APRICOT
2a
868
12%
40%
RIBAVIC
2b
400
19%
27%
Laguno
2b
95
21%
44%
Crespo
2b
121
26%
55%
Differences in Baseline Characteristics Make
Difficult a Comparison Face to Face
Fibrosis 3-4
IVDU
h ALT
Geno1
ACTG
10%
50%
67%
78%
APRICOT
12%
65%
87%
60%
RIBAVIC
40%
80%
83%
66%
Laguno
30%
85%
100%
63%
Crespo
?
79%
100%
48%
Sustained Response to HCV Therapy
HIV-neg
HIV-pos
IFN monotherapy
20%
<10%
IFN + ribavirin
45%
12-21%
Peg-IFN + ribavirin
55%
27-55%
Risk Factors for Failure of HCV Tx
•
Study of risk factors for failure
to achieve EVR to PEG-IFN +
RBV
–
–
•
Increased risk of failure with:
–
–
–
–
•
154 HIV/HCV co-infected
patients
EVR: ≥ 2 log10 c/mL ↓HCV
RNA
Serum HIV RNA
HCV genotypes 1 and 4
Abacavir use
Increased bilirubin levels
Potential drug interaction
between RBV and ABC may be
impacting outcomes
Univariate
OR
Multivariate
OR
P value
Serum HCV
RNA
2.12
2.11
0.022
HCV GT 2/3
1
HCV GT 1/4
9.82
12.13
<0.0001
d4T
0.55
ABC
3.62
4.92
0.0083
GGT (x ULN)
1.21
Bilirubin (x
ULN)
2.52
Bani-Sadr F, et al. 14th CROI, Los Angeles, CA, February 25-28, 2007.
Abst. 897.
4.52
0.0064
Abacavir Decreases SVR Rates
with HCV Treatment
•
Retrospective study of 426 HIV/HCV
patients (80% on HAART) starting pegIFN
+ RBV
•
72% did not achieve SVR
•
Lack of SVR associated with:
•
–
Higher HCV-RNA (1.92 [1.33-2.78]
<0.001)
–
GT 1/4 (4.76 [2.78-8.33] <0.001)
–
ABC use (OR 2.04 [1.08-3.85] 0.03)
ABC not associated with lower SVR if
higher RBV levels
–
•
Possible Intracellular Competition
Between Abacavir and Ribavirin
(Guanosine Analogs)
ABV
RBV
Adenosine kinase
ABV-MP
Cytosolic deaminase
CBV-MP
RBV-MP
Guanylate kinase
RBV level >2 µg/ml: 53.3% with ABC
vs 38.5% without ABC, p=0.32
CBV-DP
RBV-DP
ABC associated with a lower SVR rates
possibly due to an inhibitory competition
between RBV and ABC which are both
guanosine analogs
Nucleoside
diphospho kinase
CBV-TP
RBV-TP
Vispo E, et al. 47th ICAAC; Chicago, IL; September 17-20, 2007.
Abstract H-1731.
Abacavir does not influence the
rate of sustained virological
response in HIV-HCV
co-infected patients treated with
pegylated interferon and weight
adjusted ribavirin
Authors: Laufer N1, Laguno M1, Perez I2, Cifuentes C3,
Murillas J4, Vidal F5, Bonet L4, Veloso S5,
Gatell JM1; Mallolas J1.
*** Antiviral Therapy (submitted for publication)
% of patients with lack of response
Figure 1.Impact of Abacavir use on virologic response to pegylated
interferon plus ribavirin in HCV/HIV-coinfected patients
100
Without ABC
With ABC
90
80
70
66,04
68,89
56,41 57,14
60
50,42
50
48,28
42,86
38,1
40
31,58
35,14
30
18,18
20
7,69
10
0
Without ABC
With ABC
16,67
11,11
4
12
24
36
48
60
72
159
168
152
52
90
119
195
45
42
47
11
24
29
49
Comparison of Pegylated Interferons
•
Cohort study of PEG2A (n=315) and
PEG2B (n=242) with RBV in
HIV/HCV+, HCV Tx naïve pts (20002005)
–
–
•
•
Well matched except more F3-F4 in
PEG2B (32.8% vs 42.0%; p < 0.05)
No differences dose RBV or duration
Tx
No differences in efficacy or safety
PEG2A vs. PEG2B
Factors independently associated
with SVR
–
–
CDC clinical category (A/B vs C: 3.30
95%CI: 1.38 - 7.89, p = 0.007)
HCV genotype (GT 2/3 vs 1/4: 3.05
95%CI: 1.67 - 5.56, p<0.001)
Patient Percent
SVR by HCV Genotypes
50
45
40
35
30
25
20
15
10
5
0
46
45
19
14
Berenguer J, et al. 47th ICAAC; Chicago, IL; September 17-20, 2007.
Abstract V-1897.
G1-4
G2-3
PEG2B-RBV
PEG2A-RBV
Poster: 1018 b
A randomized trial to compare the
efficacy and safety of PEG-interferon
(PEG) alfa-2b plus ribavirin (RBV) vs
PEG alfa-2a plus RBV for treatment
of chronic hepatitis C in HIV
co-infected patients.
Laguno M1, Cifuentes C2, Murillas J3, Vidal F4, Bonet L3, Veloso S4,
Tural C5, Perez I1, Gatell JM1, Mallolas J1.
1Hospital Clínic. Barcelona. Spain. 2Hospital Son Llàtzer. Mallorca. Spain.
3Hospital Son Dureta. Mallorca. Spain. 4Hospital Joan XXIII. Tarragona. Spain.
5Hospital Germans Trias i Pujol. Badalona. Spain.
E-mail: [email protected]
Tel. +34-93-2275574
FAX. + 34-93-4514438
CROI-2008. Boston. USA
METHODS
• Prospective, randomized, multi-centre, open-label clinical trial
• Inclusion criteria:
–
–
–
–
Detectable HCV-RNA
Alanine aminotransferase >1.5-fold upper normal limit
Abnormal liver histology
CD4 counts >250 cells/mm3 and HIV-RNA <50000 copies/mL.
• Treatment arms:
PEG 2b (80-150 µg/wk adjusted to body weight)
or
PEG 2a (180µg/wk)
+ RBV (800-1200 mg/d adjusted to body weight) in both arms
• Duration of treatment: 48 weeks.
METHODS
• Primary endpoint:
– Sustained Virological Response
• (SVR= HCV-RNA negative at week 72).
• Sample size was calculated to detect, with 80%
power, differences above 20 percentual points if
they exist.
Demographics and Baseline
Characteristics
• Baseline Characteristics of 182 included patients:
Interferon (nº patients)
PEG 2b (86)
PEG 2a (96)
All (182)
Male gender #
68 (79.1)
64 (66.7)
132 (72.5)
Age (years)*
40,7 (5,0)
40,6 (5,4)
40,7 (5,2)
23,3 (6,9)
69.4 (12,3)
17.3 (6,4)
22,2 (6,6)
67.3 (10,8)
18.3 (6,0)
22,8 (6,8)
68.3 (11,5)
17.8 (6,2)
1
32 (39,5)
47 (50,5)
79 (45,4)
2
3
3 (3,7)
31 (38,3)
3(3,2)
28(30,1)
6(3,4)
59 (33,9)
4
15 (18,5)
15 (16,3)
30 (17,2)
Baseline HCV-RNA >600.000 IU/ml #
50 (60,2)
54 (58,1)
104 (59,1)
Baseline HCV-RNA >800.000 IU/ml #
Fibrosis score #
0-2
48 (57,8)
51 (70,8)
50 (53,7)
64 (71,1)
98 (55,7)
115 (70,9)
21 (29,2)
26 (28,9)
47 (29,1)
111.2 (75,3)
89.1 (47,4)
99.4 (62,9)
69 (81,2)
68 (70,8)
137 (75,7)
HMX
4 (4,7)
7 (7,3)
11 (6,1)
HTX
9 (10,6)
20 (20,8)
29 (16)
Age at HCV infection time (years) *
Baseline weight (Kg) *
Time with HCV infection (years) *
HCV Genotype #
3-4
Baseline ALT (IU/mL)*
HIV risk group #
IDU
Others
3 (3,5)
1 (1)
4 (2,1)
592.5 (269,2)
602.3 (279,6)
597.7 (274,0)
Baseline CD4 cell count >300 #
78(91,8)
88 (91,7)
166 (91,7)
HIV viral load < 200copies/mL #
63 (74,1)
70 (72,9)
133 (73,5)
Baseline CD4 cell count (cell/mL) *
* Mean (Std Desv); # Number (%)
Both groups were well
balanced:
–
72,5% males
–
76% former drug users
–
63% HCV genotype 1
or 4
–
29% bridging fibrosis
or cirrhosis
–
56% HCV viral load >
800000 IU/mL.
Demographics and Baseline
Characteristics
•
HCV Genotypes
PEG 2b
16.28
PEG 2a
3.13
15.63
5.81
37.21
48.96
29.17
36.05
4.65
3.13
Not typ Genot. 1 Genot. 2 Genot. 3 Genot. 4
RESULTS
% of response
• Global vEVR, EVR and SVR:
PEG 2b
100
90
80
70
60
50
40
30
20
10
0
PEG 2a
80,49
69,01
34,72
vEVR (week 4)
n.
72
41,86
35,06
77
EVR (week 12)
71
82
45,83
SRV (week 72)
86
96
(Primary endpoint)
RESULTS (EVR)
• Global PPV and NPV of EVR:
SVR
EVR
PEG 2b
N=49
(69%)
No SVR
SVR
n=71
No EVR
n=22
(31%)
No SVR
SVR
EVR
PEG 2a
N=66
(80%)
No SVR
SVR
n=82
No EVR
n=32 (65%)
n=17 (35%)
n=0
n=22 (100%)
n=42 (64%)
n=24 (36%)
n=0
n=16
(20%)
No SVR
n=16 (100%)
RESULTS
• vEVR, EVR and SVR by genotype:
PEG 2b
% of response
96.3
100
90
78.26
71.15
80
56.76
70
50
40
30
20.51
20
61.76
55.17
60
PEG 2a
83.33
70.97
27.66 32.26
15.69
10
0
vEVR (w eek4)
n:
39
51
EVR (w eek 12)
38
52
SRV (w eek 72)
47
Genotype 1 or 4
62
vEVR (w eek 4)
29
23
EVR (w eek 12)
30
27
Genotype 2 or 3
SRV (w eek 72)
34
31
RESULTS
• The independent factors related with SVR in the
multivariate analysis were:
– HCV genotype 2 or 3
– male gender
– age ≤40 years
Odds Ratio Estimate
Lower 95%
Confidence
Limit for Odds
Ratio
2.637
1.308
5.317 age
0.0067
PEG 2a vs PEG 2b
1.606
0.813
3.171 Interferon
0.1725
Gender:
2.828
1.241
6.447 gender
0.0134
4.618
2.317
9.202 genotype
<.0001
Effect
Age:
<= 40 years vs > 40 years
male vs female
HCV Genotype: 2+3 vs 1+4
Upper 95%
Confidence
Limit for Odds
Ratio
variable
Pr > Chi-Square
* p<0.05
er
s
mi
a
PEG 2b
Ot
h
te
tio
n
90
Hy
pe
rla
cta
l re
ac
*
Lo
ca
50
ro
mb
op
en
ia
op
en
ia
ia
% of patients
60
Th
ia
or
de
rs
An
em
dis
Le
uc
ve
es
ti
dig
pe
c
alo
iso
rd
er
s
rd
er
s
Di
so
cd
tri
Ph
yc
hia
Ge
ne
ra
l
RESULTS (AEs)
• 96% of patients presented ≥ 1 side effect.
100
PEG 2a
80
70
*
40
30
20
10
0
RESULTS (AEs)
• Adverse effects Grade III or IV.
100
90
* p<0.05
% of patients
80
70
*
*
60
50
PEG 2b
PEG 2a
40
30
20
10
0
• 10%
AE
≥ 1 AE= grade III
≥ 1 AE= grade IV
≥ 1 AE= grade III or IV
(n=19) of patients discontinuated the treatment due to
adverse effects
8% (n=7) in PEG 2b and 13% (n=12) in PEG 2a arm, (p=0.56)
RESULTS
Cumulative and number of patients with adverse events leading to
treatment discontinuation.
Number of patients
•
20
18
16
14
12
10
8
6
4
2
0
n patients
cumulative
2
4
8
12 16 20 24 28 32 36 40 44 48
Weeks
CONCLUSION
• In HIV infected patients, treatment of
chronic HCV with RBV plus PEG 2b or
PEG 2a had no statistically significant
differences in tolerance and efficacy.
Acknowledments
Infections Diseases Service:
Laguno M
Murillas J
León A
Blanco JL
García-Gasalla M
Martínez E
Milinkovic A
Loncá M
Callau P
Miró JM
Poal M
Rodriguez A
Casadesus C
García F
Gatell JM
Mallolas J
Radiology Service:
Bianchi L
Vilana R
Gilabert R
García-Criado A
Bargalló X
Hepatology Service:
Sánchez-Tapias JM
Pathology Service:
Miquel R
Biostatistics:
de Lazzari E
Pérez I
Phyquiatry Service:
Blanch J
*** To the Patients