CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

356

Methamphetamine Use in PWH on ART Is Associated With Inflammation and Residual HIV Transcription Maria Sophia B Donaire 1 , Fernanda C. Coirada 2 , Sun Jin Kim 1 , Sannidhi Sarvadhavabhatla 1 , Vivian Pae 1 , Alton Barbehenn 1 , Cassandra Yun 1 , John C. Halifax 1 , Nitasha A. Kumar 1 , Paula J. Lum 1 , Kara Lynch 1 , Steven A. Yukl 1 , Rafick P. Sekaly 2 , Susan P. Ribeiro 2 , Sulggi A. Lee 1 1 University of California San Francisco, San Francisco, CA, USA, 2 Emory University, Atlanta, GA, USA Background: High-risk people with HIV (PWH) such as individuals who use methamphetamine (MA) are most likely to benefit from HIV eradication strategies and yet they often have high rates of suboptimal ART adherence. No study to date has evaluated whether PWH with adequate viral suppression and who use MA have elevated levels of systemic inflammation and residual viral transcription during ART, which may pose additional challenges to HIV cure in this population. Methods: We performed a pilot study of 20 PWH with and without MA use (10 HIV+MA+, 10 HIV+MA-). Inclusion criteria were confirmed HIV-1 infection and undetectable viral load (<40 copies/mL) for at least 1 year. HIV+MA+ participants were sampled at 2 timepoints, and MA concentrations were quantified from plasma using a clinically validated liquid-chromatography tandem mass spectrometry (LC-MS/MS) assay. Plasma samples were also used to quantify 43 analytes using a multi-plex chemiluminescence immunoassay (MesoScale Discovery). PBMCs were used to perform reverse transcription droplet digital PCR (RT-ddPCR) assays to quantify HIV RNA transcripts produced during sequential stages of viral transcription reflecting transcriptional initiation (TAR), elongation (Long LTR), mid-transcription (Pol), distal transcription (Nef), completion (PolyA), and multiple splicing (Tat-Rev) events. Wilcoxon rank sum and signed rank tests, as well as linear regression models, were used to perform across- and within-individual comparisons. Results: HIV+MA+ and HIV+MA- groups were balanced by age, gender, race/ethnicity, nadir CD4+ T cell count, and duration of ART. Among the 43 analytes, only TNF-α, TNF-β, IL-6, and MIP-1α and IFN-β were significantly higher in HIV+MA+ vs. HIV+MA- individuals, and these associations (except IFN-β) remained statistically significant in multivariate models adjusted for nadir CD4+ T cell count and duration of ART (P<0.05). HIV RNA transcripts were detectable in a total of 17 participants. HIV Pol transcripts were significantly higher in 8 HIV+MA+ vs. 9 HIV+MA- participants. Conclusion: To our knowledge, this small pilot study is the first human study to evaluate the impact of MA use on circulating cytokine levels and the HIV reservoir during suppressive ART. MA has been shown in animal and in vitro studies to increase T cell activation and exhaustion and enhance HIV transcription. Our findings suggest that even during ART suppression, PWH who use MA may have higher levels of systemic inflammation and residual HIV transcription.

may explain the different immune response to antiretroviral therapy and to determine the metabolic pathways or biological processes that may be involved in the failure of the immune recovery process. Methods: Untargeted CD4+ and CD8+ T-cell proteomic analyse has been performed on 100 HIV-infected adult patients recruited from 5 different hospitals and classified according to their baseline CD4+ T-cell count (cases < 200 CD4+ T-cells/μl, controls ≥ 200 CD4+ T-cells/μl). Cases were divided into immunological responders (IR) or immunological non-responders (INR) based on the CD4+ T-cell counts after 48 weeks of being on ART. IRs were defined by a CD4+ T-cell count greater than 250 CD4+ T-cells/μl after treatment, and INR patients were those that showed less or equal to 250 CD4+ T-cells/μl. Results: Basal CD4+ T-cell count and CD4+/CD8+ ratio showed significant differences between groups (p<0.001 in both cases). Both CD4+ and CD8+ T-cells have shown a differential proteomic profile in INR compared to controls and IR. Alpha-1-antitrypsin (SERPINA1) and Isocitrate dehydrogenase 1 (IDH1) were two proteins with good discriminatory power between INR and IR in CD4+ T-cells using Random Forest analysis. The pathways associated with these two proteins may have a role in CD4+ T-cell death. Moreover, concerning CD8+ T-cells, Random Forest analysis has classified Carbonyl reductase [NADPH] 1 (CBR1) as a very important group differentiating variable. This protein is involved in the biosynthesis of folate, known to stimulate T-cell proliferation. Conclusion: There is a specific CD4+ and CD8+ T-cell proteomic pattern in HIV positives before undergoing ART that is distinctive among subjects initiating ART with good immune status (control), subjects initiating ART with low immune status but good immune recovery on ART (IR) and subjects initiating ART with low immune status that maintain poor immune recovery on ART (INR). The system inability to immune non-recovery of INR may include CD4+ T-cell death and CD8+ T-cell proliferation. Evaluating Biomarkers and Mortality by Sex in People With Late HIV Starting Antiretroviral Therapy Brian P Epling 1 , Jing Wang 2 , Adam Rupert 2 , Virginia Sheikh 1 , Gregg Roby 1 , Douglas Shaffer 3 , Nittaya Phanuphak 4 , Jintanat Ananworanich 4 , Frederick K. Sawe 5 , Irini Sereti 1 1 National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA, 2 Leidos Biomedical Research, Inc, Frederick, MD, USA, 3 Walter Reed Army Institute of Research, Washington, DC, USA, 4 Thai Red Cross AIDS Research Center, Bangkok, Thailand, 5 Henry M Jackson Foundation, Bethesda, MD, USA Background: In a large international study, we previously demonstrated an association between female sex and increased risk of mortality in people with HIV (PWH) with CD4 <100 cells/μL who were initiating antiretroviral therapy (ART). Our understanding of the factors underlying these differences remains incomplete. Methods: We performed a secondary analysis of data from a prospective study that included ART-naïve PWH with CD4 <100 cells/μL in the U.S., Kenya, and Thailand, who initiated ART between December 2006 to March 2013, and were followed for 48 weeks. We compared baseline differences in biomarkers using multivariable regression models, associations between the odds of death and baseline biomarkers by sex using logistic regression models, and hazards of death using Cox proportional hazards models. All analyses were adjusted for site of enrollment. Results: We assessed 506 PWH, 39.3% of whom were female (assigned sex at birth, N=199) with a median follow-up of 48 weeks. Baseline age, CD4 count, and HIV viral load were not significantly different by sex. Baseline biomarkers, including C-reactive protein (CRP), hyaluronic acid (HA), hepcidin, IP-10, IL-2, -6, -8, -10, -17, IFN-γ, myeloperoxidase (MPO), sCD14, sCD163, tissue factor, TNF, and d-dimer did not differ by sex after adjusting for multiple comparisons. The rate of CD4 recovery was higher in females than males (3 vs. 2.6 cells/μL/week, P=0.045). Within 6 months of initiating ART, 31 (6.5%) participants died, 17 of whom were female (55%). Female sex was associated with increased hazards of mortality, particularly in the first 30 days after ART initiation (HR 3.34, P=0.038). Increased CRP, increased IL-27, and decreased body mass index were associated with increased odds of death in both sexes; increased IL-8, -10, HA, MPO, and d-dimer were associated with increased odds of death in females but not males, while elevated white blood cell count and decreased hemoglobin were associated with increased odds in males but not females (Figure 1). Conclusion: We found no significant differences by sex in biomarkers, CD4 count, or viral load in PWH with CD4 <100 cells/μL starting ART. Despite a slightly higher rate of CD4 recovery, female sex was associated with increased

Poster Abstracts

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Singular CD4+ and CD8+ T-Cell Proteomic Profiles in PLHIV Immunological Non- Responders Before ART Marina Flores-Piñas 1 , Silvia Chafino 1 , Consuelo Viladés 1 , Pere Domingo 2 , Miguel López-Dupla 1 , Alexy Inciarte 3 , Jordi Navarro 4 , Julià Blanco 5 , Francesc Vidal 6 , Joaquim Peraire 1 , Anna Rull 1 1 Hospital Universitario de Tarragona Joan XXIII, Tarragona, Spain, 2 Sant Pau Biomedical Research Institute, Barcelona, Spain, 3 Hospital Clinic of Barcelona, Barcelona, Spain, 4 Vall d'Hebron Research Institute, Barcelona, Spain, 5 IrsiCaixa Institute for AIDS Research, Badalona, Spain, 6 Rovira i Virgili University, Tarragona, Spain Background: A significant proportion of people living with HIV (PLHIV) who achieve virological suppression with antiretroviral therapy (ART) fail to recover CD4+ T-cell counts, these patients are known as immunological non-responders (INR). Multiple complex mechanisms are involved in the failure of immune recovery, and intracellular proteins of CD4+ and CD8+ T-cells may have an important role. The main aim is to identify proteins, or a group of proteins, that

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CROI 2024