BACKGROUND:In a phase 1b study (NCT04811040), lenacapavir combined with the broadly neutralising antibodies (bNAbs) teropavimab and zinlirvimab maintained virological suppression (HIV-1 RNA <50 copies per mL) for 6 months in people with HIV-1 highly susceptible to both bNAbs. This phase 2 study evaluated the efficacy and safety of switching to twice-yearly lenacapavir, teropavimab, and zinlirvimab versus continuing an oral stable baseline regimen (SBR) of antiretroviral therapy (ART). Here, we report the week-26 primary efficacy endpoint results. METHODS:This randomised, open-label, phase 2 study was conducted at 34 clinical sites across Australia, Canada, and the USA. People with HIV-1 RNA who had less than 50 copies per mL on oral ART with HIV-1 highly susceptible to bNAbs teropavimab and zinlirvimab (90% inhibitory concentration ≤2 μg/mL) were randomly assigned (2:1) to receive subcutaneous lenacapavir 927 mg (plus oral loading) combined with intravenous teropavimab 2550 mg and zinlirvimab 2550 mg twice-yearly (combined treatment group), or to continue an oral SBR (SBR group). Efficacy and safety analyses included participants who received at least one complete dose of the lenacapavir, teropavimab, and zinlirvimab or SBR. The primary endpoint was the proportion of participants with HIV-1 RNA concentration of 50 copies per mL or higher at week 26. Secondary endpoints included week-26 change from baseline in CD4 cell count and safety. This study is registered with ClinicalTrials.gov, NCT05729568, and is ongoing. FINDINGS:Between May 15, 2023, and Jan 2, 2024, of 241 participants screened, 80 were enrolled. At week 26, one (1·9%; 95% CI 0·0-10·1) of 53 participants receiving twice-yearly lenacapavir, teropavimab, and zinlirvimab and zero (95% CI 0·0-12·8) of 27 participants continuing SBR had HIV-1 RNA concentration of 50 copies per mL or higher; one participant per group had no virological data (US Food and Drug Administration Snapshot Algorithm). Excluding subcutaneous lenacapavir-related injection site reactions (n=33, predominantly grade 1), treatment-emergent adverse events occurred in 36 (68%) and 17 (63%) participants in the lenacapavir, teropavimab, and zinlirvimab group and SBR group, respectively. No infusion-related reactions to bNAbs, study drug-related grade 3 or worse adverse events, serious adverse events, deaths, or adverse events leading to discontinuation occurred in the lenacapavir, teropavimab, and zinlirvimab group. INTERPRETATION:A single administration of lenacapavir, teropavimab, and zinlirvimab in the study population demonstrated similar efficacy to daily oral ART through to week 26. This regimen was well tolerated, with no serious adverse events, supporting its potential as the first complete twice-yearly, long-acting, injectable HIV-1 treatment. FUNDING:Gilead Sciences.
CD4(+) T cells are central regulators of adaptive immune responses, and their depletion following HIV infection leads to AIDS. HIV Nef and Gag weaken CD4(+) T cells by disrupting the actin cytoskeleton, which leads to impaired cell migration and immune synapse formation. Several mechanisms of cortical actin disruption have been proposed; however, a unifying and detailed mechanism has remained elusive. This study investigates how HIV alters the actin cytoskeleton of primary CD4(+) T cells, aiming to reconcile disparate mechanisms reported in the literature. Using a multi-modal approach combining ultrastructural microscopy, time-lapse imaging, small-molecule inhibitors, and proteomics, we identified potential actin regulators affected by HIV. Two distinct lamellipodial abnormalities were observed following infection, both of which are indicative of ARP2/3 inhibition. These morphologies were highly dependent on Nef in vitro and in vivo. Direct chemical inhibition of ARP2/3 recapitulated the lamellipodial defects in Nef-expressing cells. Proteomics of primary cells indicates ARP2/3 inhibition at the lamellipodia of infected T cells may occur through Nef-mediated inhibition of the WAVE2 complex, specifically via inhibitory phosphorylation of WASF2. Together with previous reports of WAVE2 regulation in HIV infection, these results support HIV Nef as a major disruptor of cortical actin through WAVE2-ARP2/3 inhibition at the lamellipodia, providing a novel mechanism of HIV-mediated CD4+ T-cell dysfunction and depletion. IMPORTANCE CD4(+) T cells migrate throughout the body and form immune synapses to carry out their functions. Both of these actions require dynamic actin structures, which are disrupted by HIV proteins. Our study suggests that a key HIV protein, Nef, might disrupt a vital internal cellular machinery that helps immune cells move and function properly. Our microscopic and proteomics studies suggest a new model in which Nef inhibits a large protein complex at the front of migrating T cells. Restoring this cytoskeletal dysfunction may be key to restoring CD4(+) T-cell survival and function, which may improve adaptive immune responses during HIV infection.
People living with HIV are at higher risk of severe illness due to common respiratory pathogens. We estimated uptake of influenza, pneumococcal, and COVID-19 vaccines among people engaged in HIV care in Ontario, Canada, and identified factors associated with vaccine uptake. We conducted a cross-sectional analysis of interviewer-administered, annual questionnaires (2021–2023) linked to medical charts and laboratory data. We used modified Poisson regression to calculate adjusted prevalence ratios and 95
OBJECTIVE:To characterize long-term cognitive trajectories in adults aging with well-controlled HIV and identify baseline predictors of cognitive decline. DESIGN:Prospective, multicenter longitudinal cohort study with repeated cognitive assessments for up to 10 years. METHODS:Positive Brain Health Now enrolled HIV+ adults aged ≥35 years without dementia and followed at 9-12-month intervals across two study phases (2013-2018; 2019-2024). Cognitive performance was assessedusing the Brief Cognitive Ability Measure (B-CAM). Group-based trajectory modeling identified patterns of cognitive change among participants with at least one visit in each phase. Baseline predictors of declining trajectory membership were examined using generalized estimating equations. RESULTS:Two cognitive trajectories were identified: one stable and one declining. Although no decline was detected during the initial 3-year follow-up, 47% of participants exhibited decline over up to 10 years, with an estimated 0.35-0.5 SD difference in B-CAM scores between trajectories.The strongest baseline predictors of decline were higher cognitive performance (floor effect), higher Framingham Risk Scoreand peripheral artery disease(OR [95% CI]: 2.84 [1.35-5.98] and 3.07 [2.06-4.57]), and older age, lower education, needing academic support, cannabis use, anxiety, low motivation, detectable plasma HIV RNA, and higher VACS Index 1.0 scores. Nadir CD4 count and HIV duration were not independently associated with decline. CONCLUSIONS:Among adults aging with well-controlled HIV, cognitive decline, when present, progressed slowly and was driven primarily by vascular risk factors, suggesting that, in the current treatment era, vascular comorbidities may play a greater role in cognitive decline than traditional HIV-related factors.
Background: Racialized immigrants are disproportionately impacted by HIV in Canada. In 2022, 69.5% of first-time HIV cases, where race and/or ethnicity was reported, were among racialized individuals: Indigenous (22.6%), Black (18.0%), Asian and Arab (16.3%), and Latinx (10.1%). HIV vulnerability in racialized communities is reinforced by HIV stigma intersecting with prejudice and discrimination associated with racism, gendered oppression, homophobia, and economic marginalization. Stigma and discrimination impede public health efforts in HIV prevention, testing, treatment, and care. Objective: The goal of the study is to reduce HIV-related stigma in racialized immigrant communities in 6 Canadian cities in Alberta (Calgary, Edmonton) and Ontario (London, Niagara, Ottawa, Toronto). We will implement an evidence-based 6-session online intervention, Acceptance and Commitment to Empowerment (ACE), to promote skills for psychological flexibility (mindfulness, acceptance, cognitive defusion, values clarification, and committed action) and collective empowerment (critical reflection, dialogue, interconnectedness, and collective action). The objectives are to (1) assess community contexts and needs to inform the refinement of ACE; (2) build community capacity in stigma reduction; (3) evaluate the facilitators and barriers of implementing stigma reduction programs; and (4) disseminate knowledge to advance research, policy, and practice. Methods: Guided by the principles of social justice and health equity, we will apply the context-based PRISM (Practical Robust Implementation and Sustainability Model) and outcome-based RE-AIM (reach, effectiveness, adoption, implementation, maintenance) frameworks to inform the contextual adaptation, implementation, and evaluation of the ACE intervention. In phase 1 (year 1), we aim to survey 12 local organizations on their existing stigma reduction programs; engage 30 service providers and 60 community members to explore the local contexts and needs of stigma reduction. In phase 2 (year 2), phase 1 results will be used to refine the ACE intervention and apply a train-the-trainer (TTT) approach to engage 48 service providers or community leaders in the ACE training. ACE TTT graduates will be mentored to become ACE Community Facilitators. In phase 3 (years 3-4), project staff and ACE Community Facilitators will work in small 3-member teams to deliver the online ACE intervention to qualified participants (n=288) in 6 cities. Mixed methods will be used to examine the contextual factors on implementation processes and intervention effectiveness. Data analyses will include reflexive thematic analysis of qualitative data, inferential statistics, and analyses of variance to determine the effectiveness of the intervention over time. Results: The implementation of project ACE was delayed by 2 years due to the COVID-19 pandemic. The requirement of obtaining research ethics approvals from all affiliated universities (n=8) further delayed the launch of research activities involving participants until September 2023. Between October 2023 and August 2024, the project team recruited 8 community leaders from the 6 project sites to form the Project Advisory Committee (PAC), worked with PAC members to identify outreach and recruitment strategies for phase 1, and recruited and secured 19 community organizations as project collaborators for phase 2. As of March 2025, phase 1 data collection has been completed, and data analysis and knowledge translation are underway. Conclusions: Based on results from previous research, we anticipate generating critical knowledge on the effectiveness of ACE in reducing internalized and enacted stigma through collective empowerment, and the facilitators/barriers in implementing ACE among racialized immigrants in real-world settings.
