CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Methods: We analyzed all the samples submitted for integrase resistance genotype (Abbot ViroSeq HIV 1 Genotyping System) to our reference laboratory from October 2021 to September 2023. Our lab that performs all the resistance tests from 25 states in México, centers that care for about 2/3 of the cases in the country. In all cases the test was ordered to detect integrase resistance. Results: Ninety-four samples were submitted to integrase resistant tests to our referral laboratory; 77(72%) have RAMs to INSTIs, but only 19 (18%) had primary resistant mutants in 12 of them accompanied by secondary mutations. The most common mutants detected were the combination of Q148H plus G140S in eight cases, all failing to DTG BID after previous failure to RAL; followed by mutation R263K present in 7 cases 6 of them detected in 2023 tests. R263K was detected in 2cases failing to DTG and 3 to Bictegravir/TAF/emtricitabine (BIC/TAF/ FTC) used as a first line treatment. All cases failing to BIC/TAF/FTC had R263K together with M50I, and were failing for at least one year, always with viremias lower than 5,000 copies/ml. Conclusion: Despite the widespread use in México of second generation INSTIs, especially after 2019 were BICTAF is used as first line treatment in close to 90% of starting cases; the number of failures is limited. Only 18% of the tests submitted had primary mutations in the integrase gene, mostly in failures after RAL use. The 3 cases of resistance to BIC/TAF/FTC in first line showed a rare mutant combination associated to low viral fitness, and are probably related to bad adherence. Virologic Outcomes With Tenofovir-Lamivudine-Dolutegravir for PI-Based Second-Line ART Failure Ying Zhao 1 , Jacqueline Voget 2 , Isaac Singini 3 , Zaayid Omar 1 , Vanessa Mudaly 2 , Andrew Boulle 1 , Gary Maartens 1 , Graeme A. Meintjes 1 1 University of Cape Town, Cape Town, South Africa, 2 Western Cape Provincial Department of Health, Cape Town, South Africa, 3 South African Medical Research Council, Cape Town, South Africa Background: Patients failing protease inhibitor (PI)-based 2nd-line antiretroviral therapy (ART) in the South African ART programme qualify for genotypic antiretroviral resistance testing (GART) – those with PI resistance receive a darunavir (DRV/r)-based 3rd-line regimen; those without PI resistance continue their regimen with adherence support. In the Western Cape Province from September 2020, an adaption to the national guideline allowed switching to tenofovir-lamivudine-dolutegravir (TLD) in such patients who had no tenofovir resistance irrespective of PI resistance. Methods: We conducted a prospective cohort study to evaluate virologic outcomes on TLD amongst consecutive adults who had virologic failure on a PI (lopinavir or atazanavir) 2nd-line regimen in whom GART was performed. We compared outcomes in patients switched to TLD between August 2019 and March 2022, and those continuing the same PI regimens or switched to DRV/r-based regimens. Patients were followed up until the primary outcome (time to HIV-1 RNA <400 copies/mL), or censored at death, loss to follow-up, or July 2023. Results: 355 patients were enrolled: 133 switched to TLD, 101 switched to DRV/r-based regimens (84% switched to DRV/r with dolutegravir), and 121 continued the same PI regimens. Median age was 40 years (IQR 34–46), 69% female, median duration on PI regimens was 65 months (IQR 34–91), median HIV-1 RNA was 4.7 log10 copies/mL (IQR 4.1–5.2) at the time of PI regimen failure. 36% and 38% had resistance to lopinavir and atazanavir, respectively. Baseline characteristics were similar between the 3 groups. In patients with PI resistance, 44/47 (94%) in the TLD group suppressed to HIV-1 RNA <400 copies/ mL compared to 89/99 (90%) in the DRV/r group (HR 1.25, 95% CI 0.86–1.82, Figure A). In patients without PI resistance, 66/86 (77%) in the TLD group suppressed to HIV-1 RNA <400 copies/mL compared to 43/120 (36%) in the continue PI group (HR 4.35, 95% CI 2.78–7.14, Figure B). Death occurred in 1/128 (0.8%) in the TLD group, 3/95 (3.2%) in the DRV/r group, and 8/114 (7.0%) in the continue PI group at 6 months. Two (2%) patients in the TLD group were known to have developed virologic failure with dolutegravir resistance at 1-3 years. Conclusion: Among patients with virologic failure on PI-based 2nd-line ART, switching to TLD when there was no PI resistance was associated with higher virologic suppression likely due to improved adherence. Virologic outcomes were similar in patients with PI resistance switched to DRV/r or TLD.

Poster Abstracts

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Phenotypic Characterization of Replication-Impaired Lenacapavir Resistant HIV Clinical Isolates Sally Demirdjian , Vidula Naik, Nicolas Margot, Brie Falkard, Christian Callebaut Gilead Sciences, Inc, Foster City, CA, USA Background: Lenacapavir (LEN) is a potent, first-in-class long-acting HIV capsid (CA) inhibitor, approved by the FDA as a twice-yearly treatment option for people living with multi-drug resistant HIV. Out of 258 people with HIV (PWH) who received LEN in clinical studies, CA mutations were observed in 14 participants (M66I, Q67H/K/N, K70H/N/R/S, N74D/H, A105T/S, and T107A/C/ N/S). Phenotypic analyses of these mutants were successful in a single cycle (SC) assay; however, in the majority of capsid mutants, replication was impaired and too low for phenotyping by the multicycle (MC) MT-2 cytopathic assay. These mutants also had low replication capacity (RC) in the SC PhenoSense Gag-Pro assay (Monogram Biosciences). Here, we have developed and optimized a novel MC phenotyping assay using a Rev-dependent HIV reporter-controlled cell line, Rev-CEM-Luc/GFP (RevLucGFP), to characterize CA mutants with low infectivity. Methods: The HIV Gag-Protease fragments from plasma samples with CA resistance mutations (CAPELLA and CALIBRATE studies, n=21) and associated site-directed mutants (SDM, n=15) were cloned into pXXLAI HIV molecular clone followed by transfection into 293T cells. Replicative viral supernatants were evaluated in 2 different MC infection formats; MT-2 and RevLucGFP cell lines, with readouts of cell viability and viral replication, respectively. Patient isolates were also evaluated in the PhenoSense Gag-Pro assay. Outputs for antiviral assays included fold change (FC) in LEN susceptibility and RC (Gag-Pro assay). Results: We successfully phenotyped 11 mutants in RevLucGFP cells that were non-infectious in MT-2 assays, including clinical isolates containing M66I in various genetic contexts and combinations of LEN resistance associated mutations (RAMs) with FC ranging from 43.5 to >1000. Antiviral activity and susceptibility in the RevLucGFP MC assay aligned with the previously observed data in the SC PhenoSense Gag-Pro assay and MT-2 cells. Additionally, we observed that SDMs generated in a clinical isolate background containing common polymorphisms have a greater ability to be phenotyped, as compared

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