Transcript Document

Mixed HCV Genotype Infection and
Response to anti-HCV treatment in
HIV/HCV Co-Infected Patients
Lucy Porrino, Sabrina Bagaglio, Giulia Morsica, Giulia Gallotta, Hamid Hasson, Laura
Galli,Vega Rusconi, Adriano Lazzarin, Caterina Uberti-Foppa
Infectious Diseases Dept, San Raffaele Scientific Institute, Milan, Italy
WEAB0102
Background
• The frequency of mixed infection in HCV monoinfection is about 213% (Schroter et al. 2003; Qian et al. 2000)
• There is a single study on viral infections with different genotypes in
HIV/HCV coinfected patients and has not been evaluated the
performance of the genotype during the anti-viral therapy (Soriano
et al. 2005)
• Previous reports from Japan identified a mutational pattern within
the core protein (70Q-91M) of HCV-1b related to the responsiveness
to standard treatment for HCV
• This finding possibly mediated by an interaction with interferon
signalling cellular protein STAT-1
AIM
To determine the HCV genotype
pattern and core domain in HIV/HCV
coinfected patients during anti-HCV
treatment
Study Patients
• A pilot clinical trial (Kamon2) was conducted to compare LPV/r
monotherapy and LPV/r-based HAART during anti-HCV therapy
• A virological sub-study was performed on patients HIV/HCV
coinfected enrolled in Kamon2
• Patients were analyzed according to response to anti-HCV treatment
Sustained Virological Response = HCV-RNA negativity at 24-weeks of
treatment and maintainment up to
(SVR)
72 weeks
No Response (NR) = ≤2 Log decrease of HCV-RNA at 12-weeks
Relapse (RE) post-treatment = HCV-RNA positivity during follow up
Methods
• Sequence analysis of HCV-5’ UTR was performed in
plasma at different time points: baseline (BL), during 48
weeks treatment and after treatment
• The entire sequence of core was inferred in plasma at
BL, during treatment and/or after treatment. All these
sequences were compared with the respective prototype
(based on HCV genotyping)
Baseline Characteristics of HIV/HCV Coinfected
Individuals According to Anti-HCV Treatment Response
All patients
SVR
NR(NR+RE)
P
(N=22)
(N=11)
(N=11)
(SVR vs NR)
Age (years)
42 (40-44)
44 (41-45)
42 (39-43)
0.95
Males/Females
13/9
6/5
7/4
1
ALT (U/I)
79.5 (59-164)
95 (74-150)
59 (45-137)
0.77
AST (U/I)
48 (36-88)
51 (41-84)
39 (29-83)
0.80
CD4+cells
count
592
(414-794)
596
(421-739)
514
(407-921)
0.70
CD8+cells
count
(cell/mmc)
925
(693-1167)
926
(837-1116)
935
(595-1258)
0.70
HCV-RNA
5.37
(4055-6.03)
6.34
(6.11-6.42)
0.05
(Log IU/ml)
6.05
(4.83-6.34)
HCV Genotype
13/9
2/9
0/11
0.0002
(cell/mmc)
(1-4 vs 2-3)
HCV Genotype Pattern in NR during
Follow-Up
 6 (55%) maintained the same HCV genotype during follow up
 5 (45%) showed an alternance of HCV genotype in plasma
BL
W4
W12
W24
W36
NR 1
1a
NA
3a
NR 2
4a
3a
4a
4a
4c/d
NR 3
1b
NA
1b
3a
NA
NR 4
1b
1b
3a
2a
1b
RE 1
1b
3a
NA
neg
neg
W48
W60
W72
lost in follow up
lost in follow up
NA
1
1b
lost in follow up
neg
neg
1b
Core sequence analysis at BL
• We obtained the core sequences of 10 SVR and 8 NR
• Different distribution of amino acids (aa) mutations in different
genotype (G)
HCV Genotype (n)
Median number of aa
mutations (IQR)
G1 (7)
1 (0-4.5)
G2 (2)
4 (3-5)
G3 (6)
6 (6-12)
G4 (3)
4 (4-4.50)
G1 vs G3
G1-G4 vs G2-G3
p= 0.018
p= 0.0276
Core sequence analysis during
follow up in 8 NR patients
• 1pt showed the same sequence at each time point
• 7 pts showed at least one aa substitution during follow up
• This aa mutation were recurrent in specific position
aa
position
20
36
70
71
75
110
N°pts
6/8
3/8
2/8
3/8
6/8
5/8
...in particular
10
20
30
40
50
....|....|....|....|....|....|....|....|....|....|
MSTNPKPQRKTKRNTNRRPQDVKFPGGGQIVGGVYLLPRRGPRLGVRATR
60
70
80
90
100
....|....|....|....|....|....|....|....|....|....|
KTSERSQPRGRRQPIPKARRPEGRTWAQPGYPWPLYGNEGCGWAGWLLSP
110
120
130
140
....|....|....|....|....|....|....|....|....|
RGSRPSWGPTDPRRRSRNLGKVIDTLTCGFADLMGYIPLVGAPLG
*epitope regions
**peptide-specific CD4+ T-cell
• 6/8 showed at least aa substitution in 1-20* and 69-75 **region
• 5/8 showed at least aa substitution in 110-115* region
• 5/8 pts showed 70Q and/or 91M
» 70Q was undetectable at BL in 3pts and
appeared during treatment
» in 1pt this mutation was detectable at BL
and disapperead during treatment
» 1pt had 91M at BL and maintained during
treatment
Characteristic mutational pattern in 2 RE at BL...
...and disappeared during follow up
NR vs RE
p= 0.0056
Conclusions - 5’ UTR analysis
• The dynamic pattern of HCV genotypes in half of
NR suggests a mixed HCV-infection
• The anti-HCV treatment may induce a change
balance of dominant strain
• Work in progress: ultradeep sequencing
(pyrosequencing) will be performed to verify
viral population in plasma
Conclusions - Core domain analysis
• At BL difficult to treat genotypes are more similar to
the respective prototype than “favourable”genotypes
• On treatment the most prominent variability of
specific residues in specific regions of the core
domain could be consequent to the pressure exerted
by interferon and/or ribavirin
Thanks to
•
Infectious Diseases Dept, San Raffaele Scientific Institute, Milan
Giulia Morsica
Sabrina Bagaglio
Marco Merli
Alice Dadda
Hamid Hasson
Giulia Gallotta
Laura Galli
Vega Rusconi
Caterina Uberti-Foppa
Adriano Lazzarin
•
•
•
National Institute of Infectious Diseases, Spallanzani, Roma
Infectious Diseases Section, Hospital SS Annunziata, Firenze
Institute of Infectious Diseases, University of Bari, Bari