CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

1 Puerta de Hierro Rsr Inst and Univ Hosp, Madrid, Spain, 2 Hosp Puerta de Hierro, Madrid, Spain, 3 Hosp de Cabueñes, Asturias, Spain Background: Oral DAA have demonstrated high efficacy for the treatment of HCV carriers. However, the presence of resistance–associated substitutions (RAS) at baseline may impair treatment response. Herein, we analyzed baseline RAS at the HCV NS5A gene region in all patients treated with DAA at one large reference clinic in Madrid. Methods: All HCV patients treated with DAA including NS5A inhibitors were retrospectively examined. Demographics and HCV genotype, baseline serum HCV-RNA, liver fibrosis staging, HIV coinfection, and sustained virological response (SVR) at week 12 were all recorded in a large database built for this study. The HCV NS5A gene region was analyzed using population sequencing at baseline in all patients as well as after 24 weeks of completing therapy in those that failed treatment. All changes recorded at NS5A positions 28, 29, 30, 31, 32, 58, 62, 92 and 93 were considered. Results: A total of 112 patients were analyzed. HCV genotype distribution was as follows: G1a (47.8%), G1b (23.5%), G3 (14.8%) and G4 (13.9%). Overall, 64 (55.6%) patients were coinfected with HIV and 55% had advanced liver fibrosis (Metavir F3-F4). Overall 57.4%were naive for HCV therapy and more than 60% had baseline HCV-RNA >6 log IU/ mL. A total of 46 (41%) patients had at least one RAS at baseline; and 6.2% had 2 or more RAS. Specific changes were as follows: M28A/G/T (4); P29S (1); Q30X (8); L31I/F/M/V (6); T58P/S (19); Q/E62D (16); A92K (1) and Y93C/H (4). Changes at position 58 were only present in genotype 4 whereas changes at position 62 were only present in genotype 3. Eleven (9.8%) patients experienced DAA failure. No association was found with high baseline HCV-RNA, HCV genotype, liver fibrosis stage, HIV coinfection, prior treatment nor specific baseline RAS. However, the presence of two or more RAS at baseline was more frequent in patients who failed compared with those that achieved SVR (18.2% vs 5%, p=0.085; respectively). Baseline NS5A resistance mutations were found at baseline in 4 out of 11 failures. They were recognized in 9 upon failure. Six patients increased the number of RAS after failure, being emerging changes Q30 (3 cases), L31 (1 case), H58 (1 case) and Y93 (2 cases). Conclusion: Baseline NS5A RAS are frequently seen (41% in our series) in HCV patients, regardless HIV status. The presence of two or more RAS may impair the likelihood of SVR. Treatment failures on NS5A inhibitors may benefit from subsequent HCV resistance testing in order to guide re-treatment options. 563 Background: Amino acid substitution at position 93 (Y93) of NS5A represents a key pathway to HCV NS5A inhibitor resistance. Multiple substitutions are associated with resistance in genotype 1a (GT1a) viruses, whereas the Y93H substitution predominates in GT1b viruses. In this study, we investigate the impact of different substitutions on NS5A inhibitor susceptibility and replication capacity (RC) in the contextof GT1a and GT1b NS5A sequences. Methods: A panel of luciferase-reporter replicons containing different Y93 substitution was constructed using H77 (GT1a) and Con1 (GT1b) NS5A sequences. NS5A inhibitor susceptibility (fold change in IC50, FC) and RC relative to the parental replicon was determined. Results: Y93C/D/F/H/L/N/R/S/T/W substitutions within the GT1a NS5A sequence generally conferred large reductions in susceptibility to ledipasvir (LDV, FC=12.2 to 159321), ombitasvir (OBV, FC=52 to 140593) and daclatasvir (DCV, FC=16 to 16523), as well as elbasvir (EBV, FC=2.6 to 49925) to a lesser extent. In contrast, Y93C/D/F/H/L/N/R/S/T/W substitutions within the GT1b NS5A sequence had much less impact on LDV (FC=0.6 to 2252), OBV (FC=0.6 to 553), DCV (FC=0.4 to 24) and EBV (FC=0.3 to 7.5) susceptibility, including, Y93H (FC=7.5 to 387). Replicons containing Y93C/L/N/R/S/T/Wwithin the GT1a NS5A sequence replicated as well as, or better than, the Y93H replicon in the presence of LDV, OBV or DCV; whereas Y93N/R/S/W replicons replicated as well, or better in the presence of EBV. Among the replicons containing GT1b NS5A sequences, the Y93H replicon replicated better in the presence of each NS5A inhibitor than all of the other replicons containing Y93 substitutions. Conclusion: Y93 substitutions confer larger reductions in NS5A inhibitor susceptibility in the context of GT1a NS5A sequences compared to GT1b sequences. Reductions in susceptibility were generally larger for LDV, OBV and DCV than EBV. Reductions in NS5A inhibitor susceptibility and RC conferred by Y93 substitutions are consistent with observed prevalence of these substitutions in GT1a and GT1b viruses. 564 NATURAL HCV RESISTANCE IS COMMON IN ITALY AND DIFFERENTLY ASSOCIATED TO GENOTYPES Valeria Cento 1 , Ada Bertoli 1 , Giustino Parruti 2 , Giuliano Rizzardini 3 , Gloria Taliani 4 , Caterina Pasquazzi 4 , Massimo Andreoni 1 , Carlo F. Perno 1 , Francesca Ceccherini Silberstein 1 , for theVIRONET-C 1 Univ of Rome Tor Vergata, Rome, Italy, 2 Pescara Hosp, Pescara, Italy, 3 Luigi Sacco Univ Hosp, Milan, Italy, 4 Sapienza Univ of Rome, Rome, Italy Background: Natural resistance associated substitutions (RASs) are reported with highly variable prevalence across different HCV genotypes (GTs) and countries. We investigated the frequency of natural RASs, and the role of NS5A-RASs on treatment efficacy, in a large Italian real-life database including the 4 main HCV-GTs. Methods: RASs in NS3 (N=1032), NS5A (N=833) and NS5B (N=496) were analysed in 1193 HCV-infected DAA-naïve patients (pts; 68% treatment-experienced; 55% cirrhotic; 5% HIV co-infected). Sanger sequencing was performed by home-made protocols on 714 GT1a, 989 GT1b, 135 GT2c, 333 GT3a, 190 GT4a/d samples. RASs with fold-change >100 were defined as major. Results: Overall, 415/1193 (35%) pts showed natural RASs, independently by cirrhosis, but with important differences for GT/subtypes. GT1a, GT1b and GT4a frequently showed NS3 RASs (52-20-36%, respectively), with high prevalence of 80K in GT1a (17%). Major RASs 168A/E/T/V had 3-4% prevalence in GT2c-GT4d. Also in NS5A, GT1a, GT1b and GT4a showed the highest prevalence of RASs (10-31-38%, respectively). NS5A RASs prevalence was higher in IFN/RBV experienced patients (35%) vs IFN-naive (22%, p=0.02) only in GT-1b. Major NS5A RASs were detected in 10% GT1a (28V-30H/R-31M-93C/H), 9% GT1b (30R-93H), 5% GT2c (31M-93H), 4% GT3a (93H) and 2% GT4d (30S). In NS5B, the sofosbuvir putative RASs 159F and 316N were exclusively detected in GT1b (13% and 19%) often in association (phy correlation=0.67, p<0.001). Among 372 pts with resistance test in all 3 genes, 10% showed multiple RASs, with frequent NS3+NS5A RASs (mainly in GT1-4). Only 2 GT1b pts showed RASs on 3 drug-targets. Lastly, 138 pts treated with a NS5A-inhibitor were studied to evaluate the potential role of natural RASs. Among 26 non-cirrhotic pts, only 4 showed baseline minor NS5A-RASs (GT1b: 30Q, 31M, 58S, 92T) and all reached a sustained viral response (SVR). Among 112 cirrhotic pts, 4 showed major baseline NS5A RASs (fold-change >1000): two pts (GT1b:93H; GT4d:30S) treated with not-recommended regimens, and without RBV, experienced virologic failure; the other 2 (GT1b:93H; GT1a:30R) received a recommended-regimen with RBV, reached SVR. Conclusion: Natural RASs are common across all HCV-GTs in Italy, and up to 10% of pts showmulti-class RASs, though only the so-called major mutations seem to have a clinical relevance. Thus, qualitative identification of only major RASs (rather than all) is required to properly guide DAA-based therapy. 565 OPTIMAL EFFICACY OF HCV-RESISTANCE–BASED RETREATMENTS AFTER PI FAILURE Valeria Cento 1 , Silvia Barbaliscia 1 , Stefano Bonora 2 , Sergio Babudieri 3 , Alessia Ciancio 4 , Giuliano Rizzardini 5 , Mario Angelico 6 , Carlo F. Perno 1 , Francesca Ceccherini Silberstein 1 , for theVIRONET-C 1 Univ of Rome Tor Vergata, Rome, Italy, 2 Univ degli Studi di Torino, Torino, Italy, 3 Univ of Sassari, Sassari, Italy, 4 City of Hlth and Sci of Turin, Turin, Italy, 5 Luigi Sacco Univ Hosp, Milano, Italy, 6 Hosp of Rome Tor Vergata, Rome, Italy Background: We analyzed the efficacy of HCV retreatment strategies after a protease inhibitor (PI) failure with various DAA regimens, and the role of resistance associated substitutions (RASs) on viral failure to a 2nd line regimen. CATALOGING THE IMPACT OF Y93 SUBSTITUTIONS ON HCV NS5A INHIBITOR SUSCEPTIBILITY Alicia Newton, Charity Ting, Arne Frantzell, Jennifer Cook, Christos Petropoulos, Wei Huang Monogram BioScis, South San Francisco, CA, USA

Poster and Themed Discussion Abstracts

CROI 2017 237

Made with FlippingBook - Online Brochure Maker