Background: Doravirine and islatravir is an investigational, once-daily, single-tablet regimen containing two potent antiretrovirals with complementary mechanisms of action and resistance profiles. We aimed to evaluate the efficacy and safety of switching from stable, oral antiretroviral therapy (ART) to the fixed combination of doravirine (100 mg) and islatravir (025 mg) in virologically suppressed adults living with HIV-1. Methods: This phase 3, randomised, active-controlled, open-label, non-inferiority trial was conducted at 53 research, community, and hospital-based clinics in eight countries: Australia, Canada, Colombia, Japan, South Africa, Switzerland, the UK, and the USA. Adults (aged >= 18 years) with a viral load of fewer than 50 copies of HIV-1 RNA per mL on any oral, two-drug or three-drug ART regimen for at least 3 months, with no history of treatment failure, known resistance to doravirine, or active hepatitis B infection, were randomly assigned (2:1) according to a computer-generated randomisation schedule (block size three) to receive oral doravirine (100 mg) and islatravir (025 mg) once daily or to continue baseline ART for 48 weeks. Randomisation was stratified by the anchor antiretroviral drug class (integrase strand-transfer inhibitor [INSTI], non-nucleoside reverse transcriptase inhibitor, or protease inhibitor) in the baseline regimen. The primary endpoint (assessed in all treated participants) was the percentage of participants with a viral load of 50 copies per mL or higher at week 48 (analysed according to the US Food and Drug Administration snapshot approach); non-inferiority would be concluded if the upper bound of the multiplicity-adjusted 95% CI for the treatment difference was less than 4%. The safety analysis population included all randomly assigned participants who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, NCT05631093, and is ongoing but closed to enrolment. Findings: Between Feb 20 and Oct 24, 2023, 614 individuals were screened for eligibility, of whom 553 were randomly assigned to receive doravirine and islatravir (n=368) or baseline ART (n=185). 551 participants received at least one dose of allocated medication: 366 in the doravirine and islatravir group and 185 in the baseline ART group. Of these 551 participants, 332 (60%) were assigned male and 219 (40%) were assigned female at birth, and the median age was 51 years (IQR 41-59); 250 (45%) identified as Black or African American and 80 (15%) identified as Hispanic, Latino, or Latina. Doravirine and islatravir showed non-inferiority at week 48, with viral loads of 50 copies per mL or higher in five (14%) of 366 participants versus nine (49%) of 185 participants on baseline ART (difference -36% [multiplicity-adjusted 95% CI -78 to -08]). Treatment-related adverse events were more common with doravirine and islatravir (44 [120%] of 366 participants) than with baseline ART (nine [49%] of 185 participants; difference 72 [95% CI 22 to 116]). Rates were similar in the doravirine and islatravir group and the baseline ART group for any adverse event (795% [291 of 366 participants] vs 838% [155 of 185 participants]; difference -43 [-107 to 28]), serious adverse events (63% [23] vs 49% [nine]; 14 [-32 to 52]), and discontinuation due to adverse events (05% [two] vs 22% [four]; -16 [-49 to 02]). One death occurred (in the baseline ART group) and was not considered treatment-related. No participants discontinued treatment as a result of protocol-specified declines in CD4 cell or total lymphocyte counts. Interpretation: Doravirine and islatravir is efficacious and well tolerated and would represent the first non-INSTI-based, two-drug regimen for HIV-1 treatment. With increasing concern over the potential development of widespread INSTI resistance, this once-daily, oral, single-tablet regimen could be a potential option for people living with HIV-1 requiring a change to their antiretroviral regimen. The safety and efficacy findings support the ongoing development of islatravir, a drug with long-acting potential.

BACKGROUND:Despite the efficacy of therapeutics and vaccines in reducing risk of severe coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections continue to occur and rebound symptoms after initial improvement have been well described. The mechanisms driving COVID-19 rebound remain unclear. METHODS:Critical inflammatory responses were assessed by Imagestream, flow cytometry, and single-cell RNA sequencing in peripheral blood mononuclear cells from vaccinated individuals presenting with early (3 days postinfection, n = 6) or late (8 days postinfection, n = 6) acute symptoms, and clinical rebound (16 days postinfection, n = 8), as well as healthy volunteers (HV, n = 7). RESULTS:An overall decline in key inflammatory responses was observed in groups with longer time from symptom onset when compared to early acute infection. However, RNA sequencing revealed a partial resurgence of inflammatory, stress, and antiviral responses during clinical rebound, with a unique cluster of monocytes with greater activation of antigen presentation pathways and type I interferon signaling. Monocytes from patients with rebound COVID-19 also showed elevated inflammasome activation when compared to HV, along with an accumulation of oxidized lipids and decreased levels of glutathione, both hallmarks of the oxidative stress response. Inflammatory measurements positively associated with serum SARS-CoV-2 nucleocapsid antigen and inversely correlated with adaptive immune responses. CONCLUSIONS:Our findings potentially reflect viral reappearance posttreatment in participants with clinical rebound and outline mechanisms by which rebound symptoms are typically milder than during acute presentations. Extending the antiviral treatment period and/or targeting inflammatory pathways could potentially prevent virological rebound or help mitigate associated symptoms. Clinical Trials Registration: NCT04401436.

BACKGROUND:Doravirine and islatravir is an investigational, once-daily, single-tablet regimen containing two potent antiretrovirals with complementary mechanisms of action and resistance profiles. We aimed to evaluate the efficacy and safety of switching from stable, oral antiretroviral therapy (ART) to the fixed combination of doravirine (100 mg) and islatravir (0·25 mg) in virologically suppressed adults living with HIV-1. METHODS:This phase 3, randomised, active-controlled, open-label, non-inferiority trial was conducted at 53 research, community, and hospital-based clinics in eight countries: Australia, Canada, Colombia, Japan, South Africa, Switzerland, the UK, and the USA. Adults (aged ≥18 years) with a viral load of fewer than 50 copies of HIV-1 RNA per mL on any oral, two-drug or three-drug ART regimen for at least 3 months, with no history of treatment failure, known resistance to doravirine, or active hepatitis B infection, were randomly assigned (2:1) according to a computer-generated randomisation schedule (block size three) to receive oral doravirine (100 mg) and islatravir (0·25 mg) once daily or to continue baseline ART for 48 weeks. Randomisation was stratified by the anchor antiretroviral drug class (integrase strand-transfer inhibitor [INSTI], non-nucleoside reverse transcriptase inhibitor, or protease inhibitor) in the baseline regimen. The primary endpoint (assessed in all treated participants) was the percentage of participants with a viral load of 50 copies per mL or higher at week 48 (analysed according to the US Food and Drug Administration snapshot approach); non-inferiority would be concluded if the upper bound of the multiplicity-adjusted 95% CI for the treatment difference was less than 4%. The safety analysis population included all randomly assigned participants who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, NCT05631093, and is ongoing but closed to enrolment. FINDINGS:Between Feb 20 and Oct 24, 2023, 614 individuals were screened for eligibility, of whom 553 were randomly assigned to receive doravirine and islatravir (n=368) or baseline ART (n=185). 551 participants received at least one dose of allocated medication: 366 in the doravirine and islatravir group and 185 in the baseline ART group. Of these 551 participants, 332 (60%) were assigned male and 219 (40%) were assigned female at birth, and the median age was 51 years (IQR 41-59); 250 (45%) identified as Black or African American and 80 (15%) identified as Hispanic, Latino, or Latina. Doravirine and islatravir showed non-inferiority at week 48, with viral loads of 50 copies per mL or higher in five (1·4%) of 366 participants versus nine (4·9%) of 185 participants on baseline ART (difference -3·6% [multiplicity-adjusted 95% CI -7·8 to -0·8]). Treatment-related adverse events were more common with doravirine and islatravir (44 [12·0%] of 366 participants) than with baseline ART (nine [4·9%] of 185 participants; difference 7·2 [95% CI 2·2 to 11·6]). Rates were similar in the doravirine and islatravir group and the baseline ART group for any adverse event (79·5% [291 of 366 participants] vs 83·8% [155 of 185 participants]; difference -4·3 [-10·7 to 2·8]), serious adverse events (6·3% [23] vs 4·9% [nine]; 1·4 [-3·2 to 5·2]), and discontinuation due to adverse events (0·5% [two] vs 2·2% [four]; -1·6 [-4·9 to 0·2]). One death occurred (in the baseline ART group) and was not considered treatment-related. No participants discontinued treatment as a result of protocol-specified declines in CD4 cell or total lymphocyte counts. INTERPRETATION:Doravirine and islatravir is efficacious and well tolerated and would represent the first non-INSTI-based, two-drug regimen for HIV-1 treatment. With increasing concern over the potential development of widespread INSTI resistance, this once-daily, oral, single-tablet regimen could be a potential option for people living with HIV-1 requiring a change to their antiretroviral regimen. The safety and efficacy findings support the ongoing development of islatravir, a drug with long-acting potential. FUNDING:Merck Sharp & Dohme, a subsidiary of Merck & Co.

BACKGROUND:Integrase strand-transfer inhibitors (INSTIs) are linked to weight gain, but data on their cardiometabolic effects, particularly major adverse cardiovascular events (MACE), are scarce. We aimed to estimate the risk of obesity, diabetes, hypertension, and MACE after switching to an INSTI in people with HIV at low-to-moderate cardiovascular risk. METHODS:In this retrospective cohort study, we used data from the global Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) to emulate a series of trials comparing switching to an INSTI versus remaining on a non-INSTI regimen on risk of incident obesity, diabetes, hypertension, and MACE. The REPRIEVE trial collected data across 12 countries from participants aged 40-75 years, on a stable antiretroviral therapy regimen for at least 6 months, with a CD4 count of >100 cells per μL, and with low-to-moderate risk for atherosclerotic cardiovascular disease. From this cohort, we included participants without a previous diagnosis of the outcomes or previous INSTI use and used data for a follow-up period of 5 years, until the outcome event, loss to follow-up, death, or study end. Data from emulated trials were pooled and hazard ratios (HRs) were estimated with weighted Cox proportional hazard models, accounting for competing events. FINDINGS:5114 participants met eligibility criteria for at least one emulated trial, representing 99 357 person-trials (median age 49 years [45-54]; 62 826 [63·2%] of 99 357 were male; 36 531 [36·8%] were female). 2981 (58·3%) of 5114 participants were captured as an INSTI switcher in at least one trial. Most switchers (2412 [80·9%] of 2981) initiated a dolutegravir-based regimen and most (47 263 [67·1%] of 70 458) non-switchers were on an efavirenz-based regimen. The HR of obesity (HR 1·41, 95% CI 1·22-1·59), diabetes (1·50, 1·24-1·81), and hypertension (1·45, 1·26-1·67) was higher in switchers than non-switchers. We did not observe an effect on MACE (1·17, 0·87-1·57). INTERPRETATION:The increase in cardiometabolic risk profile suggests long-term observation of people with HIV switching to INSTIs will be crucial to ensure appropriate management of comorbidities and to assess for future development of MACE. FUNDING:National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare.

Abstract Background An increasing proportion of people with HIV (PWH) are aged ≥ 50 years, with a greater burden of age-related comorbidities; however, long-term analyses of this population are limited. We present key treatment outcomes through 5 years of first-line therapy with bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in PWH ≥ 50 vs < 50 years. Methods Studies 1489 (NCT02607930; B/F/TAF vs dolutegravir/abacavir/lamivudine [DTG/ABC/3TC]) and 1490 (NCT02607956; B/F/TAF vs DTG+F/TAF) were randomized, double-blind, multicenter Phase 3 studies in adult PWH. This pooled analysis reports outcomes for participants ≥ 50 vs < 50 years who received B/F/TAF in the 144-week (W) randomization phase and the 96W open-label extension. Baseline demographics and clinical characteristics; proportion of participants with HIV-1 RNA < 50 copies/mL (missing=excluded); adherence; changes in CD4 cell count and metabolic, renal, and bone parameters; and treatment-emergent adverse events (TEAEs) are presented. Results Overall, 634 participants received B/F/TAF up to W240; 96 (15.1%) were ≥ 50 years and 538 (84.9%) were < 50 years. Baseline demographics, clinical characteristics, and outcomes are shown in the Table. Higher rates of baseline comorbidities were observed in those aged ≥ 50 vs < 50 years. Both groups had high rates of HIV suppression at W240. A greater proportion of participants aged ≥ 50 vs < 50 years had ≥ 95% adherence (82.8% vs 66.3%; P=0.0015). Changes in CD4 count, weight, eGFR, fasting total cholesterol to high-density lipoprotein ratio, and hip and spine bone mineral density were similar between groups. Proportions of participants with study drug-related TEAEs were similar between groups, with few participants experiencing a TEAE leading to study drug discontinuation. Proportions of TE hypertension and diabetes were modestly higher in the ≥ 50 group vs the < 50 group. Conclusion Over 5 years, participants ≥ 50 years were more likely to have high adherence to B/F/TAF treatment vs those < 50 years, with low rates of discontinuations due to AEs in both groups. B/F/TAF maintained high rates of virologic suppression, was well tolerated, and resulted in similar changes in metabolic, renal, and bone parameters in both groups, supporting its use for long-term management of HIV in older PWH. Disclosures Cissy Kityo, MD, MSc, PhD, Gilead Sciences, Inc.: Medical writing support provided by Aspire Scientific (Bollington, UK)|Janssen Pharma: Grant/Research Support Samir K. Gupta, MD, Gilead Sciences, Inc.: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support Princy N. Kumar, MD, Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Board Member|Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Medical writing support provided by Aspire Scientific (Bollington, UK)|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)|Johnson & Johnson: Stocks/Bonds (Public Company)|Merck: Advisor/Consultant|Merck: Board Member|Merck: Grant/Research Support|Merck: Stocks/Bonds (Public Company)|Moderna: Stocks/Bonds (Public Company)|Pfizer: Stocks/Bonds (Public Company)|Theratechnologies: Grant/Research Support|ViiV/GSK: Advisor/Consultant|ViiV/GSK: Board Member|ViiV/GSK: Grant/Research Support|ViiV/GSK: Stocks/Bonds (Public Company) Amy Weinberg, DNP, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Bhumi Gandhi-Patel, PharmD, Gilead Sciences, Inc.: Employee; Medical writing support provided by Aspire Scientific (Bollington, UK)|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Hui Liu, PhD, Gilead Sciences, Inc.: Employee; Medical writing support provided by Aspire Scientific (Bollington, UK)|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Jason Hindman, PharmD, MBA, Gilead Sciences, Inc.: Employee; Medical writing support provided by Aspire Scientific (Bollington, UK)|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Jürgen Rockstroh, Prof, AbbVie: Advisor/Consultant|AbbVie: Honoraria|Boehringer: Advisor/Consultant|Boehringer: Honoraria|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Gilead: Honoraria|Gilead Sciences, Inc.: Medical writing support provided by Aspire Scientific (Bollington, UK)|Janssen: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria|ViiV: Advisor/Consultant|ViiV: Honoraria

BACKGROUND:Obeldesivir is an oral nucleoside analogue prodrug antiviral that inhibits SARS-CoV-2 replication. We aimed to assess the efficacy, safety, and tolerability of obeldesivir for the treatment of COVID-19 in non-hospitalised individuals at low risk of progression to severe disease. METHODS:OAKTREE was a phase 3, randomised, double-blind, placebo-controlled trial in 107 centres (including research centres, primary care centres, and hospitals) in Japan and the USA. Low-risk, non-hospitalised adults and adolescents with mild-to-moderate COVID-19 were enrolled within 3 days of symptom onset. Eligible participants were randomly assigned 1:1 using permuted block randomisation (block size of four), stratified by historical completion of a primary COVID-19 vaccination series, to receive either oral obeldesivir 350 mg or matched placebo twice daily for 5 days. The primary efficacy endpoint was time to COVID-19 symptom alleviation by day 29, which was assessed in all randomly assigned participants who received one or more doses of study drug, had positive SARS-CoV-2 RT-PCR (per central laboratory testing) at baseline, and had COVID-19 symptom data (full analysis positive set). The primary safety endpoint was the incidence of adverse events and laboratory abnormalities and was assessed in all randomly assigned participants who received one or more doses of study drug. As a secondary endpoint we assessed change from baseline in nasal swab viral RNA copy number at day 5 in all randomly assigned participants who received one or more doses of study drug and had a quantifiable baseline value. This trial is registered with ClinicalTrials.gov, NCT05715528, and is complete. FINDINGS:Between Feb 13, 2023 and Oct 31, 2023, 1955 participants (1155 female and 800 male; 1698 White, 207 Black, 42 Asian, and eight Other) were randomly assigned and received at least one dose of either obeldesivir (n=979) or placebo (n=976). Overall, 1368 (70·0%) participants had completed a primary COVID-19 vaccination series and 1938 (99·6%) were seropositive for SARS-CoV-2 antibodies. There were 884 participants in each group in the full analysis positive set. Among those in the full analysis positive set who completed the symptom questionnaire (ie, who had COVID-19 symptom data; 879 obeldesivir, 882 placebo), median time to COVID-19 symptom alleviation was 5·9 days (95% CI 5·4-6·1) in the obeldesivir group and 6·0 days (5·8-6·3) in the placebo group (hazard ratio 1·099 [95% CI 0·997-1·211], p=0·068). The least-squares mean change from baseline in viral RNA copy number at day 5 was -2·13 log10 copies per mL (SE 0·04) and -1·95 log10 copies per mL (0·04) for the obeldesivir group (n=637) and placebo group (n=622), respectively, with a least-squares mean difference of -0·18 (95% CI -0·30 to -0·06) log10 copies per mL (p=0·0037). The safety profile was comparable between groups. 53 (5·4%) of 979 participants in the obeldesivir group and 56 (5·7%) of 976 participants in the placebo group had one or more treatment-emergent adverse events. 753 (77·5%) participants in the obeldesivir group and 757 (78·5%) participants in the placebo group had one or more graded laboratory abnormalities, most of which were grade 1 or 2. INTERPRETATION:Obeldesivir was generally safe and well tolerated, with greater reduction of SARS-CoV-2 viral RNA copy number versus placebo at day 5. However, obeldesivir did not significantly reduce time to symptom alleviation, possibly reflecting the challenges of assessing efficacy in this population in an era of high rates of vaccine-induced and natural immunity. FUNDING:Gilead Sciences.

In people with HIV (PWH), T cell immune activation and endothelial inflammation are contributors of the increased cardiovascular risk, however the mechanisms remain poorly understood. PAR1 connects the coagulation cascade, endothelial cells and CD8 T cells at the site of endothelial inflammation and we hypothesized that HIV driven CD8 T cell immune activation alters endothelial repair mechanisms. Endothelial repair is partially mediated by angiogenic T (Tang) cells that facilitate proliferation of endothelial cells, and differentiation of endothelial progenitor cells at site of vascular injury. During LCMV infection, we identified a subset of CD31highCD8 T cells that exhibited a long-lived memory precursor phenotype (CD127+KLRG1-) and secreted the proangiogenic cytokine vascular endothelial growth factor (VEGF) after viral control. Furthermore, in PWH, the frequencies of CD8 Tang cells were reduced and showed an activated phenotype and expression of granzymes. GZMA+GZMB+CD8 Tang cells correlated with atherosclerotic cardiovascular disease (ASCVD) risk. In vitro, granzyme dependent PAR1 activation led to calcium mobilization and secretion of proinflammatory cytokines IL-6, IL-8 and angiopoietin-2 by primary human endothelial cells. Altogether, these findings suggest that CD8 T cells are involved in immunity against viruses and endothelial homeostasis and HIV driven immune activation alters these functions.

We sought to understand the results of using different estimating equations (with and without a “race” category) and the addition of cystatin C as a biomarker on Chronic Kidney Disease (CKD) stage estimates among persons with HIV (PWH), for whom CKD is an important comorbidity. Biomarkers were measured in this cross-sectional single site U.S. clinic-based study from 2014 to 2016. Other laboratory and clinical data were abstracted from the electronic health record based on the last recorded value proximal to the study visit. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) glomerular filtration estimating equations with and without cystatin C were applied to categorize CKD stage, and staging agreement was assessed using the difference of proportions test. Multivariable regression analyses evaluated factors associated with CKD stage, and the Breslow-Day test evaluated whether race served as an effect modifier. Among 306 PWH, the median age was 48.2 years, 86 (28

Abstract Background Multidrug resistance arises usually in people with HIV (PWH) with extensive prior exposure to antiretrovirals (ARVs). There is a need for further understanding of factors that impact the maintenance of virologic suppression in heavily treatment experienced (HTE) PWH in a real-world setting.Table 1:Baseline Characteristics PROMISE-US 1/2* Any regimen including the two drugs and may have additional ARVs in the OBR** cGSS was calculated as per Gonzalez-Serna et al. Journal of Antimicrobial Chemotherapy, 2017, P. 496 –503, https://doi.org/10.1093/jac/dkw455. Because commercial resistance testing is not available for ibalizumab, fostemsavir, or lenacapavir, all 3 agents are always considered fully active.*** Adverse events were only collected for subjects in Cohort 2.ARV, antiretroviral; cGSS, combined genotypic sensitivity score; FTR, fostemsavir; IBA, ibalizumab; INSTI, integrase strand transfer inhibitor; LEN, lenacapavir; MVC, maraviroc; NNRTI, non-nucleotide reverse transcriptase inhibitor; NRTI, nucleotide reverse transcriptase inhibitor; OBR, optimized background regimen; PI, protease inhibitor; RNA, ribonucleic acid. Methods PROMISE-US (CT.gov Identifier: NCT05388474) is a phase 4 multicenter, retrospective and prospective, observational, non-interventional registry study. The primary objective is to evaluate the long-term efficacy and durability of ibalizumab in combination with other ARVs by comparing the clinical outcomes of patients receiving ibalizumab treatment (Cohort 2; C2) vs. matched patients not receiving ibalizumab (Cohort 1; C1). This abstract describes the study design and baseline characteristics of the first 100 patients enrolled. Baseline is defined as the date of the latest treatment change event (the start date of ibalizumab in C2; the start date of standard of care in C1). Table 1: Baseline Characteristics PROMISE-US 2/2 *Any regimen including the two drugs and may have additional ARVs in the OBR **cGSS was calculated as per Gonzalez-Serna et al. Journal of Antimicrobial Chemotherapy, 2017, P. 496 –503, https://doi.org/10.1093/jac/dkw455. Because commercial resistance testing is not available for ibalizumab, fostemsavir, or lenacapavir, all 3 agents are always considered fully active. ***Adverse events were only collected for subjects in Cohort 2. ARV, antiretroviral; cGSS, combined genotypic sensitivity score; FTR, fostemsavir; IBA, ibalizumab; INSTI, integrase strand transfer inhibitor; LEN, lenacapavir; MVC, maraviroc; NNRTI, non-nucleotide reverse transcriptase inhibitor; NRTI, nucleotide reverse transcriptase inhibitor; OBR, optimized background regimen; PI, protease inhibitor; RNA, ribonucleic acid. Results By 8-Nov-2023, a total of 114 subjects were enrolled; 70 in 1, 44 in C2. Baseline characteristics, including race, ethnicity, sex, gender, and time since diagnosis, were well matched between both cohorts. The use of ibalizumab and the combination of ibalizumab plus lenacapavir was associated with HTE patients with higher HIV viral loads and declining CD4 T cells (p-values of 0.0629 and 0.0001, respectively, for C2 vs. C1). Combined genotypic sensitivity scores (cGSSs) were comparable between the two cohorts (Table 1). However, since commercial resistance testing is not available for all newer agents, which are considered fully active, this measure may overestimate regimen sensitivity in C2 subjects who were more likely to have these in their regimens. 80% of C2 subjects had been on ibalizumab for greater than 12 months. Ibalizumab was well-tolerated with no infusion reactions reported. Conclusion Ibalizumab was more frequently selected for use in advanced HTE patients with lower CD4 cell counts and higher viral loads than other regimens. Through better understanding of HTE patients’ treatments and long-term use of ibalizumab, this study will help further characterize the efficacy and safety profile of the agents used in combination for this population with high unmet need to help guide treatment selection. Disclosures Princy N. Kumar, MD, Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Gilead: Stocks/Bonds (Public Company)|Johnson & Johnson: Stocks/Bonds (Public Company)|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Stocks/Bonds (Public Company)|Moderna: Stocks/Bonds (Public Company)|Pfizer: Stocks/Bonds (Public Company)|Theratechnologies: Grant/Research Support|ViiV/GSK: Advisor/Consultant|ViiV/GSK: Grant/Research Support|ViiV/GSK: Stocks/Bonds (Public Company) Charlotte-Paige M. Rolle, MD, MPH, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|MSD: Grant/Research Support|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Honoraria Brinda Emu, MD, Genentech/Roche: Advisor/Consultant|Theratechologies: Advisor/Consultant Zachary Henry, MD, gilead: Advisor/Consultant|theratechnology: Advisor/Consultant Claudia Martorell, MD, Gilead Sciences: Grant/Research Support|Theratechnologies: Grant/Research Support|ViiV: Grant/Research Support Jihad Slim, MD, FACP, AbbVie: Grant/Research Support|AbbVie: Honoraria|AbbVie: Speaker Bureau|Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Honoraria|Gilead Sciences, Inc.: Speaker Bureau|Merck: Grant/Research Support|Merck: Honoraria|Merck: Speaker Bureau|Theratechnologies: Advisor/Consultant|Theratechnologies: Honoraria|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Speaker Bureau R Brandon Cash, PharmD, Theratechnologies: Employee Kaitlin Anstett, PhD, Theratechnologies Inc.: Employee

Abstract Background COVID-19 continues to cause morbidity. Obeldesivir (ODV) is an oral, broad spectrum, nucleoside analog prodrug inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase. Methods OAKTREE was a Phase 3, randomized, double-blind, placebo (PBO)-controlled study in adults and adolescents without risk factors for progression to severe COVID-19. Participants were enrolled within 3 days of COVID-19 symptom onset and randomized 1:1 to receive 350 mg of ODV or PBO twice a day for 5 days. Primary endpoints were time to symptom alleviation (9 symptoms; first of 48 consecutive hours) by Day 29 and incidence of adverse events (AEs) and laboratory abnormalities. Secondary endpoints included symptom resolution and viral kinetics. Results 1955 participants were enrolled (Feb 13-Oct 31, 2023), randomized, and received ≥1 dose of study drug (98% completed study drug and the study). Baseline characteristics were similar between groups (overall mean age 41 years, 59% female, 93% Hispanic or Latino, 87% White, 11% Black, and 2% Asian). Seropositivity was >99% for SARS-CoV-2 (anti-S or anti-N) antibodies, 73% were vaccinated, and mean baseline SARS-CoV-2 viral load was 5.09 log10 copies/mL. The efficacy analysis set consisted of 1768 participants with PCR-confirmed SARS-CoV-2 at baseline. The Kaplan-Meier estimate of median time to symptom alleviation was 5.9 days (95% CI, 5.4-6.1) with ODV and 6.0 days (95% CI, 5.8-6.3) with PBO (P = 0.068). Times to symptom resolution were similar (ODV: 9.2 days [95% CI 8.9-10.0]; PBO: 9.3 days [95% CI 8.9-10.1]; P = 0.56). ODV reduced viral load at Days 3 and 5, with least squares mean treatment differences of -0.31 (P < 0.0001) and -0.18 (P = 0.0037) log10 copies/mL, respectively. The safety profile of ODV was similar to PBO, with similar rates of AEs, treatment-related AEs, serious AEs, and AEs leading to study drug discontinuation. No deaths or hospitalizations were reported by Day 29. Conclusion ODV was generally safe and well tolerated but did not significantly reduce time to symptom alleviation or resolution in a standard risk population with >99% SARS-CoV-2 seropositivity. ODV reduced SARS-CoV-2 viral load at Days 3 and 5 compared to PBO. Symptom duration was markedly shorter than in prior trials, consistent with milder disease in a population with high rates of hybrid immunity. Disclosures Onyema Ogbuagu, MD, Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Honoraria|GSK/ViiV: Advisor/Consultant|GSK/ViiV: Honoraria|Janssen: Advisor/Consultant|Moderna: Advisor/Consultant|Moderna: Honoraria Jason D. Goldman, MD, MPH, Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Speaker|Helix: Grant/Research Support Robert L. Gottlieb, MD, AbbVie: Advisor/Consultant|AbCellera: Stocks/Bonds (Public Company)|AstraZeneca: Advisor/Consultant|Eli Lilly: Advisor/Consultant|Gilead Sciences Inc.: Advisor/Consultant|Gilead Sciences Inc.: Honoraria|Gilead Sciences Inc.: travel support, gift-in-kind to his institution to facilitate an unrelated academic-sponsored clinical trial NCT03383419|GSK Pharmaceuticals: Advisor/Consultant|Johnson & Johnson: Advisor/Consultant|Pfizer: Honoraria|Regeneron: Grants or contracts to institution|Roche: Advisor/Consultant|Roivant Sciences (Kinevant Sciences): Grants or contracts to institution Upinder Singh, MD, FIDSA, Gilead Sciences, Inc.: Advisor/Consultant|Pfizer: Grant/Research Support|Regeneron: Advisor/Consultant Masaharu Shinkai, MD, PhD, AstraZeneca: Grant/Research Support|AstraZeneca: Lecture fees|Fujifilm: Grant/Research Support|Genova Inc: Grant/Research Support|Gilead Sciences, Inc.: Grant/Research Support|GSK: Grant/Research Support|GSK: Lecture fees|Kyorin Pharmaceutical: Lecture fees|Pfizer: Grant/Research Support|Sanofi: Grant/Research Support|Sanofi: Lecture fees|Shionogi: Grant/Research Support Dahlene Fusco, MD, PhD, AICURIS: Site PI|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Site PI|Metro Biotech: Site PI|Regeneron: Site PI|The Biomedical Advanced Research and Development Authority (BARDA) and the National Institute of Allergy and Infectious Diseases (NIAID): Site PI Erika Gonzalez, MD, AstraZeneca: Clinical research PI; Business relationship|DBV: Clinical research PI; Business relationship|Genentech: Clinical research PI; Business relationship|Novartis: Clinical research PI; Business relationship|Regeneron: Clinical research PI; Business relationship Princy N. Kumar, MD, Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Board Member|Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Medical writing support provided by Aspire Scientific (Bollington, UK)|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)|Johnson & Johnson: Stocks/Bonds (Public Company)|Merck: Advisor/Consultant|Merck: Board Member|Merck: Grant/Research Support|Merck: Stocks/Bonds (Public Company)|Moderna: Stocks/Bonds (Public Company)|Pfizer: Stocks/Bonds (Public Company)|Theratechnologies: Grant/Research Support|ViiV/GSK: Advisor/Consultant|ViiV/GSK: Board Member|ViiV/GSK: Grant/Research Support|ViiV/GSK: Stocks/Bonds (Public Company) Annie Luetkemeyer, MD, Cepheid: Grant/Research Support|Gilead Sciences, Inc.: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|ViiV: Grant/Research Support|Vir: Advisor/Consultant Amos Lichtman, MPH, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Afsaneh Mozaffarian, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Yiannis Koullias, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Robert H. Hyland, DPhil, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Joe Llewellyn, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Anu Osinusi, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Frank Duff, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Rita Humeniuk, PhD, Gilead Sciences, Inc.: Former Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Luzelena Caro, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Santosh Davies, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Charlotte Hedskog, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Shuguang Chen, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Kim Etchevers, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Priyanka Nadig, MPH, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Anita Kohli, MD, Eli Lilly: Received clinical trial revenue|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Received clinical trial revenue|Vir: Received clinical trial revenue

BackgroundIn people with HIV (PWH) and suppressed viral replication by antiretroviral therapy persistent T cell activation and inflammation are important contributors of the increased risk of morbidity and mortality. CD8 T cells express checkpoint receptors and are dysfunctional. IL-27, a member of the IL-6/IL-12 family has shown anti-viral properties against various human viruses, including HIV. The role of IL-27 on HIV-specific T cells remains unclear. We hypothesized that IL-27 will enhance the function of HIV-specific T cells.MethodsIL-27 effects on T cell function was evaluated by measuring cytokine secretion, proliferation, and cytotoxicity. ResultsOur findings show that IL-27 upregulates cytokine secretion and cytotoxic potential, and trafficking of proliferating HIV-specific CD8 T cells expressing checkpoint receptors TIGIT and PD-1. Unbiased clustering analysis showed that IL-27 may have differential effects on distinct populations of HIV-specific T cells. ConclusionAltogether these results suggest that IL-27 may enhance T cell function in the setting of chronic HIV infection.

Aim:Patient reported outcomes (PROs) can help to evaluate gaps and areas for improvement along the HIV care continuum. We sought to describe the methodology and processes of a PROs study within the DC Cohort study population, describe the PROs results to date, report on lessons learned, and describe future directions of the research. Subject and Methods:Each study site recruited participants from the DC Cohort, a longitudinal study on people with HIV, to complete the electronic PROs baseline and annual follow-up surveys, which consisted of previously validated measures of social determinants of health, mental health, substance use, medication adherence, and other related measures. The recruitment, enrollment, and data linkage process strengths and limitations were described. Participants' PROs survey responses were linked to their DC Cohort data to better understand participant's health overall. Results:There have been 1,739 baseline, 610 first annual, and 142 second annual completed surveys between May 2021 and May 2024. Among PROs participants, the most common reported unmet need was food insecurity (33.5%) and the most common mental health condition was generalized anxiety disorder (39.5%). A majority (59.7%) of participants reported being sexually active, but at least half did not use barrier protection. Conclusion:PROs surveys complement electronic health record data collected in the DC Cohort study, allowing for examination of health outcomes and factors collected in a longitudinal manner. PROs results could be integrated into near-real time dashboards for use by clinicians and incorporated into routine clinical care to provide a more holistic understanding of the patient.

Recurrent Clostridioides difficile infection (rCDI) often occurs after standard-of-care antibiotics. VOWST oral spores (VOS, previously SER-109), an FDA-approved orally administered microbiome therapeutic, is indicated to prevent rCDI following antibiotics for rCDI. To evaluate safety and efficacy of VOS from two phase 3 trials, (randomized, placebo-controlled [ECOSPOR III: NCT03183128] and open-label, single arm [ECOSPOR IV: NCT03183141]) of 349 adults with rCDI and prevalent comorbidities. VOS or placebo [ECOSPOR III only] (4 capsules once daily for 3 days). Integrated analysis of treatment-emergent adverse events (TEAEs) collected through week 8; serious TEAEs and TEAEs of special interest collected through week 24; and rates of rCDI (toxin-positive diarrhea requiring treatment) evaluated through weeks 8 and 24. TEAEs were mostly mild or moderate and gastrointestinal. Most common treatment-related TEAEs were flatulence, abdominal pain and distension, fatigue, and diarrhea. There were 11 deaths (3.2

Patient-reported outcomes (PROs) facilitate communication between patients and providers, enhancing patient-centered care. We report PROs for virologically suppressed people living with HIV-1 who switched to dolutegravir/lamivudine (DTG/3TC) or continued their 3- or 4-drug current antiretroviral regimen (CAR) in the phase 3 SALSA study. Secondary endpoints included change from baseline in HIV Treatment Satisfaction Questionnaire (status version; HIVTSQs) and HIV Symptom Distress Module (HIV-SDM) at Weeks 4, 24, and 48. A post hoc analysis assessed change in HIVTSQs and HIV-SDM by age (≥ 50 and < 50 years). Higher HIVTSQs scores represent greater treatment satisfaction (range, 0–60); lower HIV-SDM scores indicate less symptom bother (range, 0–80). Participants in the DTG/3TC (n = 246) and CAR (n = 247) groups reported comparable baseline HIVTSQs total scores (mean [SD], 55.2 [6.5] and 55.8 [5.5], respectively). Beginning at Week 4, mean HIVTSQs scores in the DTG/3TC group further increased vs. CAR and were sustained through Week 48. Baseline mean (SD) HIV-SDM symptom bother scores were comparable between the DTG/3TC (9.0 [9.9]) and CAR (7.9 [9.3]) groups. Small improvements in HIV-SDM scores favoring DTG/3TC were observed at Weeks 4 and 24 and sustained through Week 48 (though not significant between groups). Participants aged ≥ 50 and < 50 years who switched to DTG/3TC reported higher satisfaction and less symptom distress vs. CAR; these results were generally comparable between age groups. Participants who switched to DTG/3TC reported rapid and sustained improvements in treatment satisfaction compared with those who continued CAR, reinforcing the benefits of DTG/3TC beyond virologic suppression (NCT04021290; registration date, 7/11/2019).

BRAAVE (NCT03631732), a Phase 3b, multicenter, open-label US study, demonstrated the efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) among Black individuals with suppressed HIV through 48 weeks. Here, 72-week resistance, adherence, and virologic outcomes are presented. Enrollment criteria permitted nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistance (R), protease inhibitor (PI)-R, and certain nucleos(t)ide reverse transcriptase inhibitor (NRTI)-R (M184V/I allowed; ≥3 thymidine analog mutations [TAMs] excluded); but excluded primary integrase strand transfer inhibitor (INSTI)-R. Pre-existing resistance was determined using historical genotypes and retrospective baseline proviral DNA genotyping. Adherence, virologic outcomes, and viral blips were assessed. Of 489 participants receiving B/F/TAF with ≥1 post-switch HIV-1 RNA measurement: pre-existing NRTI-R (15% of participants), M184V/I (11%), ≥1 TAMs (8%), NNRTI-R (22%), and PI-R (13%) were observed; pre-existing INSTI-R substitutions (2%) were detected post-randomization; mean viral blip frequency was 0.9% across all timepoints (unassociated with virologic failure); 24% of participants had <95% adherence (98% of whom had HIV-1 RNA <50 copies/mL at last visit); none had treatment-emergent study-drug resistance. Overall, 99% of participants, including all with baseline NRTI-R/INSTI-R, had HIV-1 RNA <50 copies/mL at the last visit, demonstrating that B/F/TAF maintained virologic suppression through 72 weeks regardless of pre-existing resistance, viral blips, and suboptimal adherence.

IntroductionCOVID-19 patients can develop autoantibodies against a variety of secreted and membrane proteins, including some expressed on lymphocytes. However, it is unclear what proportion of patients might develop anti-lymphocyte antibodies (ALAb) and what functional relevance they might have.MethodsWe evaluated the presence and lytic function of ALAb in the sera of a cohort of 85 COVID-19 patients (68 unvaccinated and 17 vaccinated) assigned to mild (N=63), or moderate/severe disease (N=22) groups. Thirty-seven patients were followed-up after recovery. We also analyzed in vivo complement deposition on COVID-19 patients’ lymphocytes and examined its correlation with lymphocyte numbers during acute disease.ResultsCompared with healthy donors (HD), patients had an increased prevalence of IgM ALAb, which was significantly higher in moderate/severe disease patients and persisted after recovery. Sera from IgM ALAb+ patients exhibited complement-dependent cytotoxicity (CDC) against HD lymphocytes. Complement protein C3b deposition on patients’ CD4 T cells was inversely correlated with CD4 T cell numbers. This correlation was stronger in moderate/severe disease patients.DiscussionIgM ALAb and complement activation against lymphocytes may contribute to the acute lymphopenia observed in COVID-19 patients.