CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

683

Role of Dolutegravir in the Emergence of the S147G Integrase Resistance Mutation Marc Wirden 1 , Basma Abdi 1 , Sidonie Lambert-Niclot 1 , Marie-Laure Chaix 1 , Anne de Monte 2 , Brigitte Montes 3 , Coralie Pallier 1 , Pantxika Bellecave 4 , Magali Bouvier-Alias 1 , Stephanie Raymond 5 , Sabine Yerly 6 , Charlotte Charpentier 1 , Vincent Calvez 1 , Anne-Genevieve Marcelin 1 , for the French ANRS MIE Resistance Study Group 1 Assistance Publique–Hôpitaux de Paris, Paris, France, 2 Centre Hospitalier Universitaire de Nice, Nice, France, 3 University Hospital Montpellier, Montpellier, France, 4 Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France, 5 Centre Hospitalier Universitaire de Toulouse, Toulouse, France, 6 University Hospitals of Geneva, Geneva, Switzerland Background: Dolutegravir (DTG) is an integrase strand transfer inhibitor (INSTI) with high efficacy and high barrier to resistance. However some resistance mutations (RM) reduce the HIV susceptibility to this drug. While S147G RM confers high resistance to elvitegravir (EVG) in the Stanford and ANRS resistance algorithms, only STANFORD included it in the set of DTG resistance mutations. The aim of this study was to improve knowledge of S147G by specifying the context of its emergence. Methods: The databases of the French ANRS laboratories network were consulted to collect HIV strains with emergence of S147G in integrase, whatever the therapeutic context. Ongoing antiretroviral treatment, HIV-1 subtype and viral load at the time of sequencing were collected. Results: Eighty-eight strains harboring the S147G for the first time were included. The subtypes were B, CRF02, or other in 49 (55.7%), 19 (21.6%) and 20 (22.7%) cases, respectively. The median viral load and CD4 cell count were 5860 copies/mL (IQR 1011-24525) and 412 cells/ mm 3 (228-560), respectively. The INSTI included in the ongoing treatment was DTG (n=42, 48%), EVG (n=32, 36%), raltegravir (n=9, 10%), bictegravir (n=2) and cabotegravir (n=1).Two patients were not receiving INSTI: one drug-naive patient infected with a multi-resistant virus, another had received previous INSTI regimens. The median number of other INSTI-RM associated with the S147G was 2 (1.75-3.00) for all 88 patients, 3 (2.0-3.0) for those on DTG, and 2 (1-2) on EVG. Previously, among the 42 patients with emergence of S147G during DTG regimen, 9 were INSTI naive, 6 had received another INSTI without failure, 25 had failed on INSTI but without S147G for 14/25 and without resistance data for 11/25.The INSTI-RM most frequently associated with S147G under DTG were T94A (62% of cases), N155H (59%), E138K (50%), L74I/V (38%), and Q148R (33%). Nine of these 42 strains were considered resistant to DTG QD but fully susceptible to DTG BID according to ANRS algorithm, while they harbored 4 to 6 INSTI-RMs (S147G + L74I/M, E92Q, T97A, T138K, Y143C, N155H, E157Q, or S230R). These 9 patterns were associated with intermediate resistance to DTG according to Stanford algorithm. Conclusion: In this study, the S147G mutation is mainly identified during DTG regimen failures. In such a context it can be associated with up to 6 other INSTI-RM, including T97A and/or N155H in the majority of cases. Thus the S147G mutation needs to be added to the DTG resistance profile in the ANRS algorithm. HIV-1 Resistance Mutations to Integrase Inhibitors Impair Both Integration and Reverse Transcription Pauline Ratouit, Vincent Guiraud, Isabelle Malet, Cathia Soulie, Jérome Denis, Ronan Legrand, Elisa Teyssou, Anne-Genevieve Marcelin, Vincent Calvez Assistance Publique–Hôpitaux de Paris, Paris, France Background: Reverse transcription and integration are key steps of the Human Immunodeficiency Virus type 1 (HIV-1) replication, performed respectively by the viral enzyme's reverse transcriptase (RT) and integrase (IN). Interactions between these two enzymes are critical: IN improves both reverse transcription early steps and processivity, while the RT enhances the integrase strand transfer activity. The use of integrase strand transfer inhibitors (INSTIs) has led to emergence of resistant viral mutants, occurring mostly in the integrase gene. Most of them exhibit an impaired integration compared to wild-type (WT) viruses. However, their impacts on reverse transcription efficiency remain unclear. Our objective was to determine the impact of three of the main INSTI associated resistance mutation profiles, R263K, N155H and G140S/Q148H on reverse transcription and kinetics of integration. Methods: We performed in-vitro infections with wild-type and INSTI resistant viruses: R263K, N155H and G140S/Q148H, produced by site-directed mutagenesis. Early and late reverse transcription products were measured by quantitative digital-droplet PCR. Kinetics of integration were analyzed using quantitative PCR on integrated forms of HIV DNA at 24- and 72-hours post infection.

to SDMs generated in WT lab isolate background. All CA mutants with resistance to LEN remained sensitive to other main HIV drug classes. Conclusion: Using a sensitive HIV-dependent reporter-based system, we evaluated phenotypic susceptibility of several viruses with low RC (0.6-24% of WT) that were previously uncharacterized, expanding our understanding of LEN resistance and interactions between CA RAMs. Rapid Selection of HIV-2 Capsid Mutations After Failure of a Lenacapavir Containing Regimen Mélanie Bertine 1 , Gilles Peytavin 1 , Thibault Saint-Joannis 1 , Antoine Bachelard 1 , Pierre de Truchis 2 , Sylvie Lariven 1 , Philippe Morlat 3 , Cécile Pouderoux 4 , Naomi Sayre 5 , Roland Tubiana 4 , Nadia Valin 6 , Charlotte Charpentier 1 , Diane Descamps 1 , Jade Ghosn 1 , Quentin Le Hingrat 1 1 Hôpital Bichat-Claude-Bernard, Paris, France, 2 Raymond Poincaré Hôpital, Garches, France, 3 Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France, 4 Hôpitaux Universitaires Pitié Salpêtrière, Paris, France, 5 Centre Hospitalier de Saint-Denis, Saint-Denis, France, 6 Hôpital Saint-Antoine, Paris, France Background: Drug resistance is a major hurdle in the treatment of people living with HIV-2 (PLWH-2). The limited number of therapeutic options combined with the rapid selection of mutations can lead to therapeutic dead ends. Lenacapavir (LEN) is the first capsid inhibitor, with in vitro activity against both HIV-1 and HIV-2. It has been approved for PLWH-1 with multi-drug resistant viruses but its genetic barrier is low and several drug-resistance associated mutations (DRAMs) have been reported. Methods: French PLWH-2 with multi-drug resistant viruses had access to LEN through a compassionate use program. LEN was initiated along with an optimized background regimen (OBR). Plasma viral loads were measured throughout follow-up, and capsid genotyping was performed at time of virological failure using an in-house PCR assay, followed by high-throughput sequencing. Capsid sequences were compared with viral sequences obtained prior to LEN initiation to identify potential DRAMs. Results: A total of 8 PLWH-2 (4 female) initiated a treatment with LEN and an OBR. The genotypic susceptibility score (GSS) of the OBR was equal to, or below, two for all patients. Plasma viral loads at time of initiation were detectable in 6/8 patients (median: 3,830 copies/mL, range: 665-60,450). Three additional PLWH-2 achieved virological suppression within two to three months after initiating LEN+OBR. Capsid genotyping was performed on the first positive plasma viral load (median pVL: 1,600 copies/mL, range: 260-7,210). Capsid mutations were observed in six PLWH-2: five N73D mutations and one double mutation (Q66H+R69K) (Table). In addition to the N73D mutation, an A76V mutation emerged in the viruses of two patients at 11 and 17 months after initiation of LEN. Two patients (#7 and #8) had persistently high plasma viral loads but their viruses did not select any capsid mutations. Of note, the patient with the highest GSS (#4) had adherence issues, resulting in a functional monotherapy of LEN for several weeks. Conclusion: We report the rapid selection of capsid mutations in PLWH-2 failing a LEN-containing regimen. These mutations occurred at positions close to those previously reported in HIV-1. Additional data on the impact of these mutations on the phenotypic susceptibility to LEN are needed. This preliminary study underscores the low genetic barrier to resistance of LEN, especially when the GSS of the optimized background regimen is low, and the need to use it along with therapeutic drug monitoring and therapeutic education.

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Poster Abstracts

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CROI 2024 198