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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