Top 5 HIV Stories from CROI 2025: New Treatments, HIV Remission Insights, and More

Gilead's Once Yearly Lenacapavir Formulations Show Sustained Efficacy for HIV PrEP in Phase 1 Study

Moupali Das, MD, MPH, presented results from a Phase 1 study of two once-yearly intramuscular (IM) formulations of lenacapavir for HIV pre-exposure prophylaxis (PrEP). Both formulations demonstrated strong pharmacokinetic profiles, with lenacapavir concentrations sustained above the 95% effective threshold for over 56 weeks, outlasting the twice-yearly subcutaneous (SC) formulation. The median trough concentrations at Week 52 for the once-yearly formulations were 57 ng/mL and 65.6 ng/mL, compared to 23.4 ng/mL for the SC version. Additionally, peak plasma concentrations were significantly higher for the once-yearly formulations (247 ng/mL and 336 ng/mL) compared to the twice-yearly SC formulation (67.3 ng/mL). These findings indicate that the once-yearly formulations of lenacapavir not only last longer but also maintain higher plasma concentrations, suggesting enhanced efficacy and potential for improved HIV prevention. The study also confirmed that the formulations were well-tolerated, with injection site pain being the most common mild-to-moderate adverse event.

Bictegravir vs Darunavir in Advanced HIV: Results from the LAPTOP Trial

Georg Behrens, MD, PhD, presented results from the LAPTOP trial, which compared bictegravir (BIC) and darunavir (DRV) in therapy-naïve individuals with advanced HIV disease. The trial, a multi-center European study, showed that the BIC-based regimen (combined with tenofovir alafenamide and emtricitabine) outperformed the DRV-based regimen (with cobicistat, FTC, and TAF) in terms of virological suppression and immune recovery. Participants in the BIC group had a higher percentage of HIV RNA levels below 50 copies/mL and experienced faster CD4 recovery. Despite the challenges of recruiting participants with advanced HIV disease, the study demonstrated that BIC's high genetic barrier and favorable safety profile make it a potentially more effective and safer treatment option compared to DRV. Behrens highlighted that while bictegravir's advantages are clear, further long-term studies are needed to assess its continued efficacy and safety, particularly in diverse patient populations.

Immunocore Reports Some PWH Achieve Viral Control and Dose-Dependent Active HIV Reservoir Reduction in IMC-M113V Trial

Immunocore presented early findings from the Phase 1/2 STRIVE trial of IMC-M113V, a T-cell receptor bispecific therapy targeting HIV. IMC-M113V uses a bispecific protein with one end targeting HIV-infected cells and the other end recruiting T-cells to destroy these cells, specifically targeting an HLA-A*02:01-Gag complex. In the trial, 16 HIV-positive participants stable on ART showed dose-dependent viral control after ART interruption. Notably, three participants experienced delayed viral rebound, with their viral load dropping to around 200 copies/mL, a result not typically seen in untreated individuals. The therapy also led to a reduction in CD4+ T-cell-associated HIV Gag RNA, indicating a decrease in the viral reservoir. At higher doses, there was a trend toward reduced intact HIV DNA, suggesting potential for reservoir reduction. Despite mild cytokine release syndrome (CRS) at higher doses, the treatment was well tolerated. These findings support further investigation into IMC-M113V's ability to reduce the viral reservoir and potentially achieve a functional cure.

The FRESH Study Tests New HIV Remission Strategy in South African Women

Thumbi Ndung'u, BVM, PhD, presented results from the FRESH study, a Phase 2a trial investigating a combination of two broadly neutralizing antibodies (bNAbs), VRC07-523LS and CAP256V2LS, alongside the TLR7 agonist vesatolimod (VES) for HIV remission in South African women. The study involved 20 women with acute HIV-1 infection, who had been on antiretroviral therapy (ART) for at least 12 months. The regimen was well tolerated, with mild infusion-related reactions and one case of grade 1 cytokine release syndrome. Six participants maintained ART interruption for up to 48 weeks, with four continuing without ART for 55 weeks. While the combination was not fully efficacious for all participants, a subset demonstrated partial virologic control. These findings suggest potential for bNAbs and vesatolimod as part of an HIV cure strategy, especially for women, who are often underrepresented in clinical trials. Ndung'u emphasized the importance of conducting HIV cure research in resource-limited settings, highlighting its potential impact on regions like sub-Saharan Africa. Further studies will focus on understanding the immune mechanisms behind virologic control and refining the therapy for broader use.

Targeting Soluble gp120 to Combat Immune Dysfunction in People Living with HIV

Mehdi Benlarbi, a PhD student at Université de Montréal, discussed the role of soluble gp120 (sgp120) in immune dysfunction in people living with HIV (PLWH). He explained that even with undetectable viral loads on ART, sgp120 can persist in the body, contributing to chronic inflammation and hindering CD4+ T cell recovery. This insight led to the development of the RESTART study, co-designed with Andrés Finzi, PhD, which investigates whether fostemsavir, a small molecule inhibitor, can neutralize the toxic effects of sgp120 by blocking its interaction with the CD4 receptor. Madeleine Durand, MD, MSc, associate professor at the CHUM Research Centre, emphasized the study's potential to improve immune recovery and reduce cardiovascular risk in PLWH, particularly by assessing fostemsavir's effects on immune function and coronary atherosclerosis.