Transcript Diapositive 1 - Infectiologie

Current treatment of hepatitis C in
HIV co-infected patients
Dominique SALMON
Internal Medicine Department, COCHIN Hospital
Paris, FRANCE
12th ISVHLD - ANRS Co-infection day, July 5, 2006
Main points
Chronic HCV infection
Candidates
Pre therapeutic assessement
Peg IFN and RBV doses
Treatment duration
Management of adverse events
Acute HCV infection
Candidates and
Pretherapeutic assessement
Candidates to therapy
• All HCV chronically infected patients should be
offered treatment if the benefits outweigh the
risks
• CD4 < 200/mm3 : treat HIV first
• Alcoholics :
- same efficacy of PegIFN + RBV
- Pb of adherence to treatment
• Active drug users: - opiate substitution priority
- case by case evaluation
Alberti et al, 1st ECC, J Hepatol 2005
Pretherapeutic liver
evaluation
• HCV genotype
• HCV viral load
• Liver biopsy: useful, but not mandatory when a
decision to treat has been taken
• New markers of fibrosis
Impact of genotype and HCV-RNA on
SVR
% pts with SVR in APRICOT
70
> 5,9 log
UI/ml
< 5,9 log
UI/ml
60
50
40
30
20
10
0
geno 1
geno 2-3
Torriani et al NEJM 2004,
Liver biopsy in HIV/HCV coinfected patients
Not required for
treatment decision
Genotype 2 and 3
Genotype 1 and 4 , and
low HCV load (≤800,000
IU/ml)
Required for treatment
decision
 Genotype 1 and 4, and high
HCV load (>800,000 IU/ml)
 Presence of co-morbidities :
- Excessive alcohol
consumption
- HBV and/or delta co-infection
- Medication hepatotoxicity
Alberti et al, 1st ECC, J Hepatol 2005
New tests of fibrosis
FibroScan
+ seric markers
Discordance
Liver
biopsy
Concordance
Minimal fibrosis
< F2
Moderate or
severe
fibrosis F >2
Follow-up
Treatment
or
follow-up
Treatment
Castera et al. Gastroenterology 2005; 128: 343-50.
Doses of Peg IFN and ribavirin
Doses of Peg-IFNa
100
• Peg-IFNa 2a 180 mg/w
• Peg-IFNa 2b 1.5 mg/kg/w
SVR (%)
80
60
40
44
40
27
27
20
0
APRICOT
ACTG 5071
Peg-IFN 2a
RIBAVIC
LAGUNO
Peg-IFN 2b
SVR with PegIFN + RBV in HIV/HCV
patients
APRICOT ACTG
5071
RIBAVIC LAGUNO
40%
27%
27%
44%
Genotype 62%
2-3
44%
27%
53%
Genotype 29%
1
17%
14%
(1 and 4)
Gobal
38%
(1 and 4)
Dose of ribavirin is critical
Genotype 2 or 3
Genotype 1 or 4
Low ARN HCV
< 800 000 UI/ml
Ribavirin 800 mg
High ARN HCV
> 800 000 UI/ml
Ribavirin 1000-1200 mg
Alberti et al, 1st ECC, J Hepatol 2005
Dose of ribavirinin 2006
Genotype 2 or 3
Genotype 1 or 4
Whatever
HIV-RNA
Ribavirin 800 mg
Ribavirin 1000-1200 mg
Alberti et al, 1st ECC, J Hepatol 2005
Increased ribavirine dose useful in
genotype 1 with high viral load (WIN-R)
Group A: PEG-IFNα-2b + ribavirin 800 mg/d
vs.
Group B: PEG-IFNα-2b. + ribavirin 13 + 2 mg/kg
G1: 48 week
p = 0.047
SVR (%)
40
27
30
32
20
10 n=
725 776
0
Genotype 2, 3
p = 0.173
39
34
65 68
SVR (%)
Genotype 1
G2-3 : 24 sem. vs. 48 week
70
n=
446 391
Viral load
Viral load
> 600 000 Ul/ml < 600 000 Ul/ml
58 60
0
322 316
588 602
24 weeks
48 weeks
Jacobson et al. LB3, AASLD 2005
PRESCO trial
n=389
Peg-IFN + RBV
1000-1200 mg/day
G1,4
Follow-up
G1,4
G2,3
Follow-up
G2,3
0
12
24
Follow-up
Follow-up
36
48
60
72
84
Study weeks
Only patients who achieved EVR (>2 log drop in HCV-RNA at week 12) continued treatment.
96
APRICOT (800mg/d) vs PRESCO and FRIED
(1000-1200 mg/d) : genotype 1 response
Percentage of patients
100%
90%
80%
70%
46%
60%
34%
50%
36%
31%
40%
29%
Apricot
Presco
Fried
30%
20%
13%
10%
0%
<50UI/ml W4
On-treatment analysis
SVR
Soriano, ICAAC 2006, accepted
Relation between RBV concentration and
sustained virologic response in Co-infected
patients
3,5
D4 W2 W3
RBV Concentration (mg/L)
3
Virologic failure
Virologic succes
2,5
2
1,5
1
0,5
0
0
1
2
3
4
5
6
7
8
Time (hours)
9
10
11
12
13
14
Breilh D., Abstract 928, CROI 2005
Recommended treatment
duration
= 48 weeks
Positive predictive value of early
virological response (EVR) on SVR
All
Genotype Genotype
genotypes
1
2/3
EVR at W12
> 2 log drop HCV
RNA
EVR at W4
> 2 log drop HCV
RNA
undetectable
HCV-RNA
56 %
45 %
70 %
66 %
58 %
74 %
83%
82%
94%
Torriani, NEJM, 2004, 292;
Probability of success is
evaluable as early as W4
HCV-RNA
undetectable
SVR probability
83%
geno 1
58%
>2 log HCV-RNA
decrease
SVR probability
60%
geno 2/3
74%
Negative predictive value of
early virological response (EVR)
All
Genotype Genotype
genotypes
1
2/3
No EVR at W12
< 2 log drop HCV
RNA
-
98 %
100 %
No EVR at W4
< 2 log drop HCV
RNA
88 %
90 %
84 %
Torriani, NEJM, 2004, 292;
Early viral Kinetics in RIBAVIC trial
VPP
94
100
80
VPN
99
82
71
60
40
20
0
W4
W12
Carrat et al. JAMA 2004
Duration of treatment
Evaluate at week 12
early virological response
HCV-RNA
 > 2 log
Treatment
for 48 weeks
If HCV-RNA neg at W24
HCV-RNA 
< 2 log
TTT should be
stopped
Alberti et al, 1st ECC, J Hepatol 2005
Optimal duration for genotype
2,3 in HIV co-infected patients ?
Optimal duration for genotype
2,3 in HIV co-infected patients ?
Keep patients on the optimal dose
of peg-IFN and ribavirin
Apricot Ribavic ACTG
5071
Laguno
 dose
AE
Lab abnormality
25%
18%
16%
20%
pegIFN RBV
10%
25% 31%
34%
18%
Tx interruption
25%
39%
31%
23%
Proactive management of adverse events
and antiretroviral treatment
Torriani NEJM 2004;Carrat Jama 2004; Chung,NEJM 2004; Laguno AIDS 2004
Impact of adherence on SVR with
PegIFNa 2a /ribavirin bitherapy
SVR depends on RBV doses within the 12 first weeks
70
60
66
50
p=0.01
57
40
45
30
20
10
0
0
>97 %
80 -97 %
60 -80 %
<60 %
Reddy et al. EASL 2005
Prevention and proactive
management of adverse events
Influenza-like syndrome
paracetamol
+/- NSAID
Depression
Manage depressive
mood changes
Anemia
Hb < 8 g/dl : 3.8%
Neutropenia
avoid AZT
Use EPO
Use G-CSF
Mitochondrial toxicity (1-3%)
Liver decompensation
No ddI (d4t) : RR X
2.3
Hyper or hyothyroidism
betablockers
levothyroxin
keep > 95% of the dose mainly for the first 3 months
RIBAVIC – Mitochondrial toxicity
(pancreatitis –hyperlactatemia)
• Incidence
– 27,5 / 1000 pat./year (all)
– 34,1 / 1000 pat./year (with ARV)
– 0 / 1000 pat./year (without ARV)
ddI
d4T
% with
mitochondrial
toxicity
Yes
Yes
24 %
Yes
No
7%
No
Yes
0%
Non
No
2%
Multivariate analysis : odds-ratio for ddI = 23 [95 % CI : 5-105]
Carrat et al. JAMA 2004; 292: 2839-2848
AZT: impact on anemia and RBV
doses
3,14
Hb (g/dl)
3
1,96
2
1
0
AZT
No AZT
Alvarez D et al. 12th Conference on Retroviruses and Opportunistic Infections
(Abstract #: P-192). Boston, MA USA, February 22–25, 2005
RBV dose decrease at W4
Patients with RBV dose decrease
Hb decrease at
W4
60 %
52 %
40 %
20 %
20 %
0%
AZT
No AZT
Impact of Epoetin alfa
40
Epoetin alfa
% Change from Study Entry
35
Placebo
30
/Epoetin alfa
25%
25
†
*
15
5
23%
22%
20
10
§
/Epoetin alfa
12%
‡
14%
9%
11 %
8% 9%
6%
5%
0
-5
-1%
Week 9
Week 17
Physical
Week 9
Week 17
Mental
Week 9
Week 17
Vitality
*p = 0,009 ; †p < 0,001 ; ‡p < 0,03 ; §p = 0,003 ; Epoetin alfa vs. Placebo.
Afdhal et al. Gastroenterology 2004
Management of non responders
Was the treatment adequate ?
No
Yes
Adherence Pb,
side effects,
low doses
100% of the dose
during the first 12 W
Partial response
or relapse
Retreatment
No response
= true
non responder
Approach dependent on histology :
• Minimal disease => wait new drugs
• Significant disease (F3-F4) =>
– Monitor ESLD and HCC
– Consider alternative strategies
Maintenance
therapy
Retreatment
HAART
High dose peg-IFN?
New drugs ?
Acute HCV treatment
Treatment of acute HCV hepatitis
• 168 HCV monoinfected: ALT (5-10x), PCR and/or
sero-conversion
• Egypt, USA, Germany
• Geno 1, 4: 60%
• 1.5mg/kg/wk PEG a2b for 12 weeks
• Initiation from 1st positive RNA result either at :
SVR (%)
Time of Rx onset
Intent to Rx
Treated
8 weeks (n=43)
95%
95%
12 weeks (n=43)
93%
91%
20 weeks (n=82)
77%
70%
Kamal et al Gastroenterology 2006;130:632-8
Treatment of acute HCV
Geno 1
Geno 2+3
Geno 4
Kamal et al Gastroenterology 2006;130:632-8
Comparison of the 2 largest studies
of acute HCV infection
Kamal et al
Wiegard et al
N° patients
168
89
Rx duration
12 weeks
24 weeks
SVR
95% (early Rx)
89%
Main group
Occ exposure: 56%
IDU, sex: 44%
+ve factors
Geno non-1
ALT >500
•PEG alone 12 weeks as good as 24 weeks
•Delay up to 12 weeks max from diagnosis
•Max chance of SVR for geno 2 or 3
Kamal et al Gastroenterology 2006;130:632-8; Wiegand et al Hepatology 2006; 43: 250-6
Treatment of acute HCV hepatitis
in HIV infection
Initiation from PCR/seroconversion at 12 weeks
N°
Regimen
Duration
(weeks)
genotype
% SVR
Vogel M
et al
11
Variable
23-48
GT 1/4 : 10
Other: 1
91%
Gilleece YC
et al
27
PegIFN +RBV
24
GT 1: 20
Other : 4
55%
100%
Dominguez S 14
et al
PegIFN + RBV
24
GT 1/4 : 8
Other: 3
71.4%
Vogel et al, J Viral Hepatitis, 2005; Gilleece et al, J AIDS 2005;Dominguez S et al, submitted
Conclusion (1)
• As eradication is possible, hepatitis C treatment
discussed for all patients, except if minimal liver
disease
• Histological evaluation crucial: liver biopsy should
not be an obstacle new tools available.
• Improved success rates with HCV therapy due to:
– proactive management side effects
– increased ribavirine dose (1000-1200mg
genotype 1)
Conclusion (2)
• Duration of treatment (48 weeks) depends on EVR:
– at 12 weeks : stop if no significant response
– at 24 weeks : stop if viral load remains positive.
• Fields of research :
– Geno1, high VL : higher doses RBV and/or Peg
IFNa ?
– Slow responders : longer duration of therapy ?
– True non responders: maintenance therapy ?
– New molecules.