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Treatment of Chronic Hepatitis C in HCV-HIV Infected Patients. J Mallolas Infectious Diseases Service Hospital Clínic Barcelona. Why to treat HCV in HIV patients ?. Why to treat HCV in HIV patients ?. Longer survival Faster progression to cirrhosis Higher mortality due to ESLD - PowerPoint PPT Presentation
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Treatment of Chronic Hepatitis C in HCV-HIV
Infected Patients
J Mallolas
Infectious Diseases ServiceHospital Clínic
Barcelona
1. Why to treatHCV 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
HAART: Highly Actibe Antiretroviral Therapy ( 2NRTI plus 1PI/NNRTI)
Effect of HIV on HCV Liver Fibrosis Progression Rate
Benhamou et al. Hepatology 1999;30:1054.
4
3
2
1
0
403020100
Duration of HCV Infection (years)
Fib
ros
is G
rad
es
(ME
TA
VIR
Sc
ore
)
HIV+ (n = 122)
Matched controls (n = 122)
Simulated controls (n = 122)
Increase with CD4 <200/mm3, ETOH, age
Causes of death per year in HIV patientsHospital Clínic. Barcelona
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1997 1998 1999 2000 2001
Cardiovascular causes
Accidental causes
Neoplasias
End-stage liver disease
AIDS-related illnesses
Risk factors of Hepatotoxicity in HCV-HIVcoinfected patients:
Author No. ART HCV CD4 Rate Predictors
Rodriguez1 132 PI-based 62% 324 11% HCV Alc.
Sulkowski2 211 PI-based 51% 109 12% HCV
CD4
Saves3 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
52
30
44
21
0
20
40
60
80
100
% o
f p
atie
nts
VR SVR
PEG + RBV (n=52) IFN + RBV (n=43)
P=0.033P=0.017
AIDS 2004, 18:F27–F36
Response by Genotype 1-4, ITT
41
11
38
7
0
20
40
60
80
100
% o
f p
atie
nts
VR SVR
PEG + RBV (n=52) IFN + RBV (n=43)
P=0.011
P=0.007
AIDS 2004, 18:F27–F36
Response by Genotype 2-3, ITT
68 67
5347
0
20
40
60
80
100
% o
f p
atie
nts
VR SVR
PEG + RBV (n=19) IFN + RBV (n=15)
P=0.914
P=0.730
AIDS 2004, 18:F27–F36
0
20
40
60
80
100
Adverse Events
% o
f pat
ient
sSide effects (I)
• 92% of patients developed adverse events.
Side effects (II)
• Premature discontinuation: 19% (Peg 23 vs 14%); 15% due to side effects (17 vs 12%)
– 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
0
5
10
15
20
Pre
ma
ture
c
um
ula
tiv
e
dis
co
nti
nu
ati
on
%
2 4 8 12 16 40
PEG+RBV
INF+RBV
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
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%
Superiority of Peg IFN-Ribavirin (Sustained Virological Response)
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
– 154 HIV/HCV co-infected patients
– EVR: ≥ 2 log10 c/mL ↓HCV RNA
• Increased risk of failure with:– 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 4.52 0.0064
Bani-Sadr F, et al. 14th CROI, Los Angeles, CA, February 25-28, 2007. Abst. 897.
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
– RBV level >2 µg/ml: 53.3% with ABC vs 38.5% without ABC, p=0.32
• ABC associated with a lower SVR rates possibly due to an inhibitory competition between RBV and ABC which are both guanosine analogs
Vispo E, et al. 47th ICAAC; Chicago, IL; September 17-20, 2007. Abstract H-1731.
Possible Intracellular Competition Between Abacavir and Ribavirin (Guanosine
Analogs)
Possible Intracellular Competition Between Abacavir and Ribavirin (Guanosine
Analogs)
RBVRBV
RBV-MPRBV-MP
RBV-DPRBV-DP
RBV-TPRBV-TP
CBV-MPCBV-MP
CBV-DPCBV-DP
CBV-TPCBV-TP
ABVABV
ABV-MPABV-MP
Guanylate kinaseGuanylate kinase
Nucleoside diphospho kinase
Nucleoside diphospho kinase
Cytosolic deaminaseCytosolic deaminase
Adenosine kinaseAdenosine kinase
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)
Figure 1.Impact of Abacavir use on virologic response to pegylated interferon plus ribavirin in HCV/HIV-coinfected patients
50,42
56,41
68,89
42,86
35,14
18,18 16,67
48,28
57,14
7,69
31,58
66,04
38,1
11,11
0
10
20
30
40
50
60
70
80
90
100
% o
f p
atie
nts
wit
h l
ack
of
resp
on
se Without ABC
With ABC
4 12 24 36 48 60 72
159
45
168
42
152
47
52
11
90
24
119
29
195
49
Without ABC
With ABC
Comparison of Pegylated Interferons
• Cohort study of PEG2A (n=315) and PEG2B (n=242) with RBV in HIV/HCV+, HCV Tx naïve pts (2000-2005)
– 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)
SVR by HCV Genotypes
Pat
ient
Per
cent
Berenguer J, et al. 47th ICAAC; Chicago, IL; September 17-20, 2007. Abstract V-1897.
14
46
19
45
05
101520253035404550
G1-4 G2-3PEG2B-RBVPEG2A-RBV
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: mallolas@clinic.ub.esTel. +34-93-2275574
FAX. + 34-93-4514438
CROI-2008. Boston. USA
Poster: 1018 b
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)
orPEG 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:
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.
* Mean (Std Desv); # Number (%)
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)
Age at HCV infection time (years) * 23,3 (6,9) 22,2 (6,6) 22,8 (6,8)
Baseline weight (Kg) * 69.4 (12,3) 67.3 (10,8) 68.3 (11,5)
Time with HCV infection (years) * 17.3 (6,4) 18.3 (6,0) 17.8 (6,2)
HCV Genotype # 1 32 (39,5) 47 (50,5) 79 (45,4)
2 3 (3,7) 3(3,2) 6(3,4)
3 31 (38,3) 28(30,1) 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 # 48 (57,8) 50 (53,7) 98 (55,7)
Fibrosis score # 0-2 51 (70,8) 64 (71,1) 115 (70,9)
3-4 21 (29,2) 26 (28,9) 47 (29,1)
Baseline ALT (IU/mL)* 111.2 (75,3) 89.1 (47,4) 99.4 (62,9)
HIV risk group # IDU 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)
Others 3 (3,5) 1 (1) 4 (2,1)
Baseline CD4 cell count (cell/mL) * 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)
Demographics and Baseline Characteristics
• HCV Genotypes
5.81
37.21
4.6536.05
16.283.13
48.96
3.13
29.17
15.63
Not typ Genot. 1 Genot. 2 Genot. 3 Genot. 4
PEG 2b PEG 2a
RESULTS
• Global vEVR, EVR and SVR:
35,06
80,49
45,83
69,01
34,7241,86
0102030405060708090
100
vEVR (week 4) EVR (week 12) SRV (week 72)
PEG 2b PEG 2a
(Primary endpoint)
% o
f r
esp
on
se
n. 72 77 71 82 86 96
32
RESULTS (EVR)
SVR
n=71
n=32 (65%)
n=17 (35%)
n=22 (31%)
n=0
n=22 (100%)
EVR
No EVR
No SVRSVR
No SVR
N=49(69%)
PEG 2b
n=82
n=42 (64%)
n=24 (36%)
n=16(20%)
n=0
n=16 (100%)
EVR
No EVR
SVR
No SVRSVR
No SVR
N=66(80%)
PEG 2a
• Global PPV and NPV of EVR:
RESULTS
• vEVR, EVR and SVR by genotype:
71.15
32.26
78.26
96.3
70.9761.76
55.17
27.6620.51
56.76
83.33
15.69
0
10
20
30
4050
60
70
80
90
100
vEVR (week4) EVR (week 12) SRV (week 72) vEVR (week 4) EVR (week 12) SRV (week 72)
PEG 2b
PEG 2a
Genotype 1 or 4 Genotype 2 or 3
% o
f r
esp
on
se
n: 39 51 38 52 47 62 29 23 30 27 34 31
RESULTS
• The independent factors related with SVR in the multivariate analysis were:– HCV genotype 2 or 3
– male gender
– age ≤40 years
Effect Odds Ratio Estimate
Lower 95% Confidence
Limit for Odds Ratio
Upper 95% Confidence
Limit for Odds Ratio variable Pr > Chi-Square
Age: <= 40 years vs > 40 years 2.637 1.308 5.317 age 0.0067
PEG 2a vs PEG 2b 1.606 0.813 3.171 Interferon 0.1725
Gender: male vs female 2.828 1.241 6.447 gender 0.0134
HCV Genotype: 2+3 vs 1+4 4.618 2.317 9.202 genotype <.0001
0
10
20
30
40
50
60
70
80
90
100
Genera
l Diso
rders
Phychi
atric d
isorde
rs
alope
cia
diges
tive dis
orders
Anemia
Leuc
open
ia
Thrombo
penia
Loca
l reac
tion
Hyperla
ctatem
iaOthe
rs
% o
f p
ati
en
ts
PEG 2b PEG 2a
RESULTS (AEs)
• 96% of patients presented ≥ 1 side effect.
* *
* p<0.05
• Adverse effects Grade III or IV.
• 10% (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)
0
10
20
30
40
50
60
70
80
90
100
AE ≥ 1 AE= grade III ≥ 1 AE= grade IV ≥ 1 AE= grade III or IV
PEG 2bPEG 2a
RESULTS (AEs)
**
* p<0.05
% o
f p
atie
nts
RESULTS
• Cumulative and number of patients with adverse events leading to treatment discontinuation.
02468
101214161820
2 4 8 12 16 20 24 28 32 36 40 44 48
n patients
cumulative
Nu
mb
er o
f p
atie
nts
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 MMurillas JLeón ABlanco JLGarcía-Gasalla MMartínez EMilinkovic ALoncá MCallau PMiró JMPoal MRodriguez ACasadesus CGarcía FGatell JMMallolas J
Radiology Service:Bianchi LVilana RGilabert RGarcía-Criado ABargalló X
Hepatology Service:Sánchez-Tapias JM
Pathology Service:Miquel R
Biostatistics:de Lazzari EPérez I
Phyquiatry Service:Blanch J
*** To the Patients
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