CROI 2024 Abstract eBook

Abstract eBook

Oral Abstracts

covered time with DCP vs SoC was 65.6% and 52.8% higher for men and women, respectively. Intervention effect on coverage during periods at risk of HIV was larger; mean at-risk covered time was 76.5% in the DCP arm vs. 16.2% in SoC (difference 60.2%; 95%CI: 53.8-66.6%; p<0.001). In the DCP arm, 56%, 53%, 2% ever used CAB-LA, PrEP or PEP, respectively. 43% of persons who used CAB-LA were not using prior oral PrEP or PEP, showing benefit of adding the CAB- LA option. 28% and 0.4% of participants used at least 2 different products in the DCP and SoC arms, respectively. There were 7 participants who acquired HIV infection and one perinatal transmission in the SoC arm (incidence rate: 1.8%) and 0 in the DCP arm (p=0.01). Conclusion: In the first randomized study of a person-centered model offering structured choice between CAB-LA, oral PREP and PEP with option to change over time, enrolling both women and men at risk of HIV, the SEARCH DCP intervention increased biomedical covered time by >5 fold to 69.7% and reduced HIV incidence to 0% compared to 1.8% in standard-of-care. Selection of Epigenetically Privileged HIV-1 Proviruses During Treatment With Panobinostat and IFNα Marie Armani-Tourret 1 , Ciputra Adijaya Hartana 1 , Isabelle Roseto 1 , Leah Carrere 1 , Amy Sbrolla 2 , Katrina Shea 2 , Theresa Flynn 2 , Liliana Vela 1 , Alexander Hochroth 1 , Frederic D. Bushman 3 , Rajesh T. Gandhi 2 , Ce Gao 1 , Xu G. Yu 1 , Daniel R. Kuritzkes 4 , Mathias Lichterfeld 1 1 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 2 Massachusetts General Hospital, Boston, MA, USA, 3 University of Pennsylvania, Philadelphia, PA, USA, 4 Brigham and Women's Hospital, Boston, MA, USA Background: CD4 T cells with latent HIV-1 infection persist despite treatment with currently available antiretroviral agents and represent the main barrier to HIV-1 cure. Pharmacological disruption of viral latency may increase the immunological vulnerability of HIV-1 infected cells, but the efficacy of latency reversing agents for reducing HIV-1 persistence remains to be proven Methods: We conducted a randomized controlled human clinical trial in which panobinostat (PBT), a potent histone deacetylase inhibitor (HDACi), was evaluated in combination with pegylated IFNα2a (PEG-IFNα2a). ART-treated participants were randomized to receive PBT alone (n=4), the combination of PBT and PEG- IFNα2a (n=9) or PEG-IFNα2a alone (n=4). We quantified CD4 T cell-associated HIV-1 RNA by RT-ddPCR and proviral HIV-1 DNA using the intact proviral DNA assay (IPDA). Cellular immune responses were analyzed by flow cytometry and CD4 T cell gene expression profiling was conducted by RNA-Seq. The integration sites were collected using ISLA or LM-PCR and we conducted a genome-wide assessment of H3K27ac histone marks using CUT&RUN sequencing. Results: The combined treatment with PBT and PEG-IFNα2a increased CD4 T cell-associated HIV-1 RNA (fold increase 1.83, p=0.0029). In parallel, the study medication induced activation of cDC2, pDCs, and cytotoxic NK cells and enhanced the expression of IFN-stimulated genes. The combined treatment also resulted in a trend for reduced frequencies of intact proviruses, determined by IPDA (p=0.0547). To evaluate effects of the study medication on the proviral landscape, we collected 2,695 integration sites; these studies showed that the combined treatment induced a structural transformation of the HIV-1 reservoir cell pool, characterized by an accumulation of HIV-1 proviruses integrated in ZNF genes (p=0.032), in chromatin regions with reduced H3K27ac marks, and, to a lesser extent, in centromeric/satellite DNA regions. Conclusion: Treatment with PBT and PEG-IFNα2a can induce notable changes in the proviral reservoir landscape, with preferential elimination of proviruses in proximity to H3K27ac marks, the molecular target site for PBT. Together, these results provide proof-of-principle that the viral reservoir is vulnerable to "shock and kill" interventions. Role of Cytoskeleton and Adhesion in a Rare Subset of HIV-Infected Cells That Resist CTL Louise Leyre 1 , Farah Mustapha 2 , Alberto Herrera 1 , Paul Zumbo 1 , Micheal Galiano 2 , Jared Weiler 1 , Doron Betel 1 , Morgan Huse 2 , R. Brad Jones 1 1 Weill Cornell Medicine, New York, NY, USA, 2 Memorial Sloan Kettering Cancer Center, New York, NY, USA Background: Although latency is a key mechanism of HIV persistence, the reservoir continues to be shaped by cytotoxic T lymphocytes (CTL) pressure under antiretroviral therapy (ART). Growing evidence suggests that this selects for reservoir-harboring cells with CTL-resistant properties, including over expression of BCL-2, PVR and the granzyme B inhibitor SERPINB9. Here, we lay a foundation for identifying novel mechanisms by comprehensively profiling

for 6 months. At screening, all were asked about their HIV testing history and prior results. Reporting includes only South Africa and Eswatini, where recency testing is complete. Incidence estimates used ABIE v3. Results: In South Africa and Eswatini, 2682 women were screened (87% of the INSIGHT cohort) and 119 (4.4%) tested HIV-positive, among whom 6 were classified as recent infections (27 had LAg avidity ODn≤1.5 and 21 had VL<1000 copies/ml, Figure A), for an estimated HIV incidence rate (IR) of 0.71 (95% CI 0.14-1.28). Among the 2487 in the HIV-negative cohort followed for 6 months, 97% accepted TDF/FTC PrEP, and there were 17 incident infections, IR=1.23/100 p-y (95% CI 0.77-1.97). 1909 (71%) of this cohort self-reported an HIV test within the past 6 months, including 51 HIV-positive at screening who self-reported a prior HIV negative test (Figure B). Among these 51 possible new infections, 39 had VL obtained; 23/39 (59%) had VL<1000 copies/ml, suggesting ART had been initiated. If the remaining 16/1909 were infections occurring in the prior 6 months, this would be consistent with an IR of at least 1.7/100 p-y, although self-reported test timing and results were unverified. Conclusion: In this first reported use of recency testing during screening of women in Africa, estimated incidence using recency was lower than our observed incidence in prospective follow-up with high PrEP uptake and recent placebo incidence rates of 3-4% in HIV prevention trials. Cross-sectionally assessed HIV incidence may have been underestimated due to 1) selection bias if HIV testing is frequent and women with HIV are reluctant to screen, and 2) viral suppression from undisclosed early ART. Understanding sources of bias is critical for refining the recency approach and obtaining accurate contemporary HIV incidence estimates.

Oral Abstracts

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Randomized Trial of SEARCH Dynamic Choice HIV Prevention Including Injectable Cabotegravir (CAB-LA) Moses R Kamya 1 , Laura B. Balzer 2 , James Ayieko 3 , Jane Kabami 4 , Elijah Kakande 4 , Gabriel Chamie 5 , Nicole Sutter 5 , Helen Sunday 4 , John Schrom 5 , Melanie Bacon 6 , Catherine A. Koss 5 , Alex R. Rinehart 7 , Maya L. Petersen 2 , Diane V. Havlir 5 , for the SEARCH Consortium 1 Makerere University, Kampala, Uganda, 2 University of California Berkeley, Berkeley, CA, USA, 3 Kenya Medical Research Institute, Nairobi, Kenya, 4 Infectious Diseases Research Collaboration, Kampala, Uganda, 5 University of California San Francisco, San Francisco, CA, USA, 6 National Institute of Allergy and Infectious Diseases, Gaithersburg, MD, USA, 7 ViiV Healthcare, Research Triangle Park, NC, USA Background: We hypothesized that an oral PrEP, PEP and CAB-LA biomedical prevention package with structured choice between products and opportunities to switch would increase biomedical prevention coverage compared to standard-of-care (SoC) among men and women at risk for HIV in rural Uganda and Kenya. Methods: Participants were recruited from three randomized studies of the SEARCH dynamic choice HIV prevention (DCP) intervention vs SoC in antenatal clinics, outpatient departments and the community. Eligible participants were > 15 years and reported risk of acquiring HIV. Participants in the SoC arm had access to oral PrEP (TDF/XTC) and PEP (TLD) at local Ministry of Health (MoH) clinics. The SEARCH DCP model included person-centered, structured choice between oral PrEP, PEP (MoH-supplied) or CAB-LA (study-supplied at MoH clinics) and the ability to switch between or stop products over time based on patient product preference and risk. Primary outcome was biomedical covered time over 48 weeks (proportion of follow-up covered by PrEP/PEP/CAB-LA), assessed via study logs and self-report; secondary outcomes included coverage during periods of retrospectively self-assessed HIV risk and incident HIV infections. Results: We enrolled 984 participants (487 DCP; 497 SoC). 73% were women, 30% aged 15-24. Mean biomedical covered time was higher in DCP (69.7%) vs. SoC (13.3%), a difference of 56.4% (95% CI 50.8- 62.1%; p<0.001). Biomedical

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CROI 2024