BACKGROUND:Antiretroviral therapies with long dosing intervals have the potential to improve virological outcomes and treatment satisfaction for people with HIV-1. We report the primary endpoint results from week 48 of ISLEND-2, a phase 3 trial evaluating the efficacy and safety of switching to once-weekly oral islatravir-lenacapavir from daily oral standard of care in virologically suppressed adults with HIV-1. METHODS:This randomised, open-label, active-controlled, phase 3 non-inferiority trial was conducted at 100 sites in 14 countries and territories. Eligible participants were adults (aged ≥18 years) with HIV-1 who had been virologically suppressed on daily oral standard-of-care treatment for at least 6 months and had no previous virological failure. Participants were randomly assigned (1:1), using interactive response technology and stratified by geographical region, antiretroviral class, and CD4+ T-cell count, to switch to the once-weekly, single-tablet oral regimen of islatravir (2 mg)-lenacapavir (300 mg) or to continue daily oral standard of care for at least 96 weeks. The primary endpoint was the proportion of participants with an HIV-1 RNA viral load of 50 copies per mL or higher at week 48 (as per the US Food and Drug Administration-defined Snapshot algorithm), with a non-inferiority margin of 4%, assessed in all randomly assigned participants who received any dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT06630299, and is active but closed to new participants. FINDINGS:From Oct 8, 2024, to April 30, 2025, 727 participants were screened, of whom 647 were eligible for the study, 634 were randomly assigned, and 626 received treatment: 314 with islatravir-lenacapavir and 312 with standard of care. Of 626 participants, 211 (34%) were female, 193 (31%) were Black, 119 (19%) were Asian, 123 (20%) were Hispanic or Latine, and 89 (14%) were aged 65 years or older. At baseline, 552 (88%) were on a single-tablet antiretroviral regimen and 478 (76%) were receiving regimens containing integrase strand transfer inhibitors. At week 48, one (0·3%) of 314 participants in the islatravir-lenacapavir group and four (1·3%) of 312 participants in the standard-of-care group had an HIV-1 RNA viral load of 50 copies per mL or higher (difference -1·0% [95·002% CI -3·0 to 1·1]), meeting the non-inferiority criteria. Treatment-related adverse events occurred in 58 (18%) of 314 participants in the islatravir-lenacapavir group and one (<1%) of 312 participants in the standard-of-care group. Two (1%) of 314 participants in the islatravir-lenacapavir group and one (<1%) of 312 participants in the standard-of-care group discontinued the study owing to adverse events, with adverse events of grade 3 or higher occurring in 24 (8%) and 28 (9%) participants and serious adverse events in 22 (7%) and 27 (9%) participants in the islatravir-lenacapavir group and standard-of-care group, respectively. There were three deaths: one in the islatravir-lenacapavir group and two in the standard-of-care group, none of which were considered treatment-related. INTERPRETATION:Once-weekly islatravir-lenacapavir showed non-inferior efficacy to the standard of care and was generally well tolerated. Longer-term safety data will provide further valuable insights beyond the week 48 data presented here. Islatravir-lenacapavir has potential to be the first once-weekly complete oral single-tablet regimen for HIV-1 treatment. FUNDING:Gilead Sciences and Merck Sharp & Dohme.

BACKGROUND:Once-daily, single-tablet regimens have transformed care for persons living with human immunodeficiency virus type 1 (HIV-1); however, challenges to adherence continue to limit effective treatment. Long-acting oral-drug combinations could offer new options with less frequent dose administration. METHODS:We conducted a phase 3, double-blind, randomized, active-controlled, noninferiority trial in 12 countries to evaluate the efficacy and safety of a switch to once-weekly oral islatravir-lenacapavir (ISL/LEN) from once-daily oral bictegravir-emtricitabine-tenofovir alafenamide (B/F/TAF) in adults in whom HIV-1 had been virologically suppressed for at least 6 months while they were receiving B/F/TAF. Participants were assigned in a 1:1 ratio to receive once-weekly ISL/LEN (2 mg/300 mg) or to continue once-daily B/F/TAF for 96 weeks; all received matched placebo for the alternative regimen. The primary end point was the percentage of participants with an HIV-1 RNA level of 50 copies per milliliter or higher at week 48, as determined by the Food and Drug Administration-defined snapshot algorithm. Noninferiority was determined at a margin of 4 percentage points. RESULTS:A total of 607 participants underwent randomization; 304 were assigned to the ISL/LEN group and 303 to the B/F/TAF group. A total of 21% of the participants were women, 31% were Black, 26% were Hispanic or Latine, and 15% were 65 years of age or older. At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was reported in no participants in the ISL/LEN group and 1 (0.3%) in the B/F/TAF group (difference, -0.3 percentage points; 95.002% confidence interval [CI], -1.4 to 0.8); an HIV-1 RNA level of less than 50 copies per milliliter was reported in 284 (93.4%) and 280 (92.4%), respectively (difference, 1.0 percentage point, 95% CI, -3.2 to 5.2). The mean change in the CD4+ T-cell count at week 48 was -10 cells per microliter with ISL/LEN and -18 cells per microliter with B/F/TAF (least-squares mean difference, 12 cells per microliter; 95% CI, -16 to 39). The trial regimen was discontinued owing to adverse events in 6 participants (2.0%) in the ISL/LEN group and 5 (1.7%) in the B/F/TAF group; serious adverse events occurred in 16 (5.3%) and 14 (4.6%), respectively. CONCLUSIONS:Among persons with virologically suppressed HIV-1, once-weekly oral ISL/LEN was noninferior to once-daily B/F/TAF in maintaining HIV viral load suppression. (Funded by Gilead Sciences and Merck Sharp and Dohme; ISLEND-1 ClinicalTrials.gov number, NCT06630286.).

Building on results from the AELIX-002 trial with HIVACAT T-cell immunogen (HTI)-based vaccines, the AELIX-003 (NCT04364035) trial tested the safety of the combination of ChAdOx1.HTI (C) and MVA.HTI (M), with the TLR7 agonist vesatolimod (VES), in a double-blind, placebo-controlled, randomized clinical trial in 50 virally suppressed early-treated men with HIV-1 infection. Secondary objectives included immunogenicity and effects on viral rebound kinetics during a 24-week antiretroviral treatment interruption (ATI). The most common treatment-related adverse events were mild-to-moderate injection-site pain, influenza-like illness, headache, and fatigue. Strong, broad, and HTI-focused T-cell responses were induced by vaccination. All participants experienced viral rebound in ATI; 33.3% and 23.5% (P = 0.4494) of CCMM + VES and placebo recipients, respectively, remained off antiretroviral therapy for 24 weeks. Post hoc analysis confirmed a correlation between levels of HTI-specific T cells and prolonged time off antiretroviral therapy. The combination of HTI vaccines and VES was safe and elicited robust T-cell responses.

BACKGROUND:Randomized, placebo-controlled clinical trials (RCTs) that include analytical treatment interruptions (ATI) are conducted to test the efficacy of HIV cure strategies. Two independent RCTs, AELIX-002 and AELIX-003, evaluated the HTI immunogen-based vaccines alone or combined with the TLR7 agonist vesatolimod in early-treated people with HIV (etPWH). These studies individually demonstrated that higher levels of vaccine-induced HTI-specific T-cell responses were associated with extended time off antiretroviral therapy (ART) during a 24-week ATI. METHODS:We conducted a pooled analysis of both RCTs including the individual data of a total of 88 participants. The association between clinical, immunogenicity and viral data and rebound outcomes during the ATI was evaluated using logistic regression and receiver operating characteristic (ROC) analyses. RESULTS:We identify an HTI-specific threshold of 835 spot-forming cells/106 peripheral blood mononuclear cells as a predictor of delayed and slower viral rebound during ATI. This threshold distinguishes participants who remain off ART for >12 weeks, with 58% sensitivity, 85% specificity, 75% positive and 73% negative predictive value. CONCLUSIONS:These findings confirm that HTI-specific T-cell magnitude at ATI initiation is the strongest predictor of ATI outcomes observed in AELIX002/003 studies and that a threshold of vaccine-induced HTI-specific T-cell responses can be used as futility criteria before ATI and/or guide participant selection in future HTI-based HIV cure trials aimed at achieving therapy-free remission.

The only current strategy to test efficacy of novel interventions for sustained HIV control without antiretroviral therapy (ART) among people with HIV (PWH) is through an analytical treatment interruption (ATI). Inclusion of 'placebo' controls in ATIs poses ethical, logistical, and economic challenges. To understand viral dynamics and rates of post-treatment control (PTC) after ATI among PWH receiving either placebo or no intervention, we undertook an individual-participant data meta-analysis. In total, 24 eligible prospective studies with 382 individuals with >= 5 plasma HIV RNA viral loads (pVLs) within the first 84 days post-ATI were included. Early-ART was defined as ART initiation within 6 months of HIV acquisition; others were classified as late-ART or unknown. Median age was 42 years, 91% male, 75% white, 45% received early-ART. Median time to pVL >50, >400, and >10,000 copies/mL was 16 days (interquartile range [IQR]:13-25), 21 (IQR:15-28), and 32 (IQR:20-35), respectively. PTC defined as pVL <50 copies/mL at day 84 occurred in 4% (n = 14) of participants (6% early-ART and 1% late-ART). Sustained PTC of pVL <50 copies/ml after 84 days is rare in PWH, especially in those starting ART late. Our findings inform future interventional HIV cure/remission trials on study size and design.

While therapeutic vaccines are a promising strategy for inducing human immunodeficiency virus (HIV) control, HIV vaccines tested to date have offered limited benefit to people living with HIV. The barriers to success may include the use of vaccine platforms and/or immunogens that drive weak or suboptimal immune responses, immune escape and/or immune dysfunction associated with chronic infection despite effective antiretroviral therapy. Combining vaccines with immune modulators in a safe manner may address some of the challenges and thus increase the efficacy of therapeutic HIV vaccines. We evaluated the immunogenicity of a ChAd68/samRNA-based simian immunodeficiency virus (SIV) vaccine regimen alone and in combination with a series of immune modulators in a preclinical rhesus macaque (M. mulatta) model. The vaccine was co-delivered with the checkpoint inhibitors αPD-1 or αCTLA-4, or with a FLT3 receptor agonist (FLT3Ra) shown to differentiate and expand dendritic cells and improve T cell priming. We demonstrate that the magnitude, breadth and functionality of SIV-specific vaccine-elicited CD8+ T cell responses were enhanced by combination with either αPD-1, αCTLA-4, or FLT3Ra. Combination with FLT3Ra also expanded polyfunctional CD4+ T cell responses. Our data demonstrate enhanced and distinct shaping of vaccine-elicited immune responses by immune modulators with implications for developing a functional HIV cure.

The identification of therapeutic strategies to induce sustained antiretroviral therapy (ART)-free control of HIV infection is a major priority.1 Combination immunotherapy including HIV vaccination, immune stimulation/latency reversal, and passive transfer of broadly neutralizing antibodies (bNAbs) has shown promise in non-human primate models,2-7 but few studies have translated such approaches into people. Here, we performed a single-arm, proof-of-concept combination study of these three approaches in ten people with HIV on ART that included (1) therapeutic vaccination with an HIV/Gag conserved element (CE)-targeted DNA+IL-12 prime/MVA boost regimen followed by (2) administration of two bNAbs (10-1074 and VRC07-523LS) and a toll-like receptor 9 (TLR9) agonist (lefitolimod) during ART suppression, followed by (3) repeat bNAb administration at the time of ART interruption. Seven of the ten participants exhibited partial (low viral load set point) or complete (aviremic) post-intervention control after stopping ART, independent of residual bNAb plasma levels. Robust expansion of activated CD8+ T cells early in response to rebounding virus correlated with lower viral load set points. These data suggest that combination immunotherapy approaches might prove effective to induce sustained control of HIV by slowing rebound and improving CD8+ T cell responses, and that these approaches should continue to be optimized.

Vesatolimod (VES), a toll-like receptor 7 agonist, is being investigated as part of a strategy for human immunodeficiency virus (HIV) cure. VES is metabolized through the CYP3A pathway and is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). This study evaluated the impact of coadministration of VES with cobicistat (COBI; a P-gp, BCRP, and strong CYP3A inhibitor) or voriconazole (VOR; a strong CYP3A inhibitor with no effect on transporters) on the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of VES in people with HIV (PWH). A total of 15 people with virally suppressed HIV on antiretroviral therapy received 2 mg VES (on day 1 in period 1, day 2 in period 2, and day 3 in period 3), 150 mg COBI once daily for 5 days in period 2, and 400 mg VOR on day 1 and 200 mg twice daily on days 2–6 in period 3. Blood samples were collected to measure VES PK, expression of interferon-stimulated genes (ISGs), cytokine/chemokine levels, and immune-cell phenotyping. Coadministration of VES with VOR did not impact VES PK. In contrast, coadministration of COBI increased VES maximum plasma concentration (Cmax), area under the concentration–time curve extrapolated to infinity (AUCinf), and half-life (t1/2) 7.5-, 4.3-, and 1.2-fold, respectively, but did not increase the mRNA expression levels of ISGs, serum cytokines/chemokines, or expression of activation markers on peripheral natural killer or T cells compared with VES alone. There were no serious adverse events, and no participants discontinued study drugs due to study-drug-related adverse events. VES was well tolerated when administered alone or in combination with COBI or VOR in PWH. Coadministration of COBI, but not VOR, increased plasma VES concentrations, suggesting that inhibition of transporters (P-gp and/or BCRP) may have a greater impact on VES PK than inhibition of the drug-metabolizing enzyme (CYP3A). ClinicalTrials.gov NCT05458102.

BACKGROUND:A key research priority for developing an HIV cure strategy is to define the viral dynamics and biomarkers associated with sustained post-treatment control. The ability to predict the likelihood of sustained post-treatment control or non-control could minimize the time off antiretroviral therapy (ART) for those destined to not control and anticipate longer periods off ART for those destined to control. METHODS:Mathematical modeling and machine learning were used to characterize virologic predictors of long-term virologic control using viral kinetics data from several studies in which participants interrupted ART. Predictors of post-ART outcomes were characterized using data accumulated from the time of treatment interruption, replicating real-time data collection in a clinical study, and classifying outcomes as either post-treatment control (plasma viremia ≤400 copies/mL at 2 of 3 time points for ≥24 weeks) or non-control. RESULTS:Potential predictors of virologic control were the time to rebound, the rate of initial rebound, and the peak plasma viremia. We found that people destined to be non-controllers could be identified within 3 weeks of rebound (prediction scores: accuracy, 80%; sensitivity, 82%; specificity, 71%). CONCLUSIONS:Given the widespread use of analytic treatment interruption in cure-related trials, these predictors may be useful to increase the safety of analytic treatment interruption through the early identification of people who are unlikely to become post-treatment controllers.

Background A key research priority for developing a human immunodeficiency virus (HIV) cure strategy is to define the viral dynamics and biomarkers associated with sustained posttreatment control. The ability to predict the likelihood of sustained posttreatment control or noncontrol could minimize the time off antiretroviral therapy (ART) for those destined to be controllers and anticipate longer periods off ART for those destined to be controllers.Methods Mathematical modeling and machine learning were used to characterize virologic predictors of long-term virologic control, using viral kinetics data from several studies in which participants interrupted ART. Predictors of post-ART outcomes were characterized using data accumulated from the time of treatment interruption, replicating real-time data collection in a clinical study, and classifying outcomes as either posttreatment control (plasma viremia, <= 400 copies/mL at 2 of 3 time points for >= 24 weeks) or noncontrol.Results Potential predictors of virologic control were the time to rebound, the rate of initial rebound, and the peak plasma viremia. We found that people destined to be noncontrollers could be identified within 3 weeks of rebound (prediction scores: accuracy, 80%; sensitivity, 82%; specificity, 71%).Conclusions Given the widespread use of analytic treatment interruption in cure-related trials, these predictors may be useful to increase the safety of analytic treatment interruption through early identification of people who are unlikely to become posttreatment controllers.

HIV infection is associated with gut dysbiosis, and microbiome variability may affect HIV control when antiretroviral therapy (ART) is stopped. The TLR7 agonist, vesatolimod, was previously associated with a modest delay in viral rebound following analytical treatment interruption in HIV controllers (HCs). Using a retrospective analysis of fecal samples from HCs treated with vesatolimod or placebo (NCT03060447), people with chronic HIV (CH; NCT02858401) or without HIV (PWOH), we examined fecal microbiome profile in HCs before/after treatment, and in CH and PWOH. Microbiome diversity and abundance were compared between groups to investigate the association between specific phyla/species, immune biomarkers, and viral outcomes during treatment interruption. Although there were no significant differences in gut microbiome diversity between people with and without HIV, HCs, and CH shared common features that distinguished them from PWOH. there was a trend toward greater microbiome diversity among HCs. Treatment with vesatolimod reduced dysbiosis in HCs. Firmicutes positively correlated with T-cell activation, while Bacteroidetes and Euryarchaeota inversely correlated with TLR7-mediated immune activation. Specific types of fecal microbiome abundance (e.g. Alistipes putredinis ) positively correlated with HIV rebound. In conclusion, variability in the composition of the fecal microbiome is associated with markers of immune activation following vesatolimod treatment and ART interruption.

Vesatolimod is a Toll-like receptor-7 (TLR7) agonist in clinical development as part of a combination regimen for human immunodeficiency virus (HIV) cure. Influenza-like symptoms associated with TLR7-mediated immune activation have been reported in clinical trials of vesatolimod. Therefore, a broader understanding of the safety profile of vesatolimod and association with dose and mechanism of action will help inform future clinical studies. In this analysis, data on flu-like adverse events of interest (AEIs) were pooled from eight clinical studies in which 606 participants either received single or multiple doses of vesatolimod (0.3–12 mg; n = 505) or placebo (n = 101). Vesatolimod pharmacokinetics, inflammatory responses, and pharmacodynamics were assessed. The incidence of flu-like AEIs was higher with vesatolimod versus placebo (19

BackgroundAntiretroviral therapy (ART) for HIV-1 treatment has improved lifespan but requires lifelong adherence for people living with HIV (PLWH), highlighting the need for a cure. Evaluation of potential cure strategies requires analytic treatment interruption (ATI) with close monitoring of viral rebound. Predictive biomarkers for HIV-1 rebound and/or duration of control during ATI will facilitate these HIV cure trials while minimizing risks. Available evidence suggests that host immune, glycomic, lipid, and metabolic markers of inflammation may be associated with HIV-1 persistence in PLWH who are treated during chronic HIV-1 infection.MethodsWe conducted post-hoc analysis of HIV controllers who could maintain low levels of plasma HIV-1 without ART in a phase 1b vesatolimod trial. Baseline and pre-ATI levels of immune, glycomic, lipidomic, and metabolomic markers were tested for association with ATI outcomes (time of HIV-1 rebound to 200 copies/mL and 1,000 copies/mL, duration of HIV-1 RNA ≤400 copies/mL and change in intact proviral HIV-1 DNA during ATI) using Spearman’s correlation and Cox proportional hazards model.ResultsHigher levels of CD69+CD8+ T-cells were consistently associated with shorter time to HIV-1 rebound at baseline and pre-ATI. With few exceptions, baseline fucosylated, non-galactosylated, non-sialylated, bisecting IgG N-glycans were associated with shorter time to HIV rebound and duration of control as with previous studies. Baseline plasma MPA and HPA binding glycans and non-galactosylated/non-sialylated glycans were associated with longer time to HIV rebound, while baseline multiply-galactosylated glycans and sialylated glycans, GNA-binding glycans, NPA-binding glycans, WGA-binding glycans, and bisecting GlcNAc glycans were associated with shorter time to HIV rebound and duration of control. Fourteen bioactive lipids had significant baseline associations with longer time to rebound and duration of control, and larger intact proviral HIV-1 DNA changes; additionally, three baseline bioactive lipids were associated with shorter time to first rebound and duration of control.ConclusionConsistent with studies in HIV non-controllers, proinflammatory glycans, lipids, and metabolites were generally associated with shorter duration of HIV-1 control. Notable differences were observed between HIV controllers vs. non-controllers in some specific markers. For the first time, exploratory biomarkers of ATI viral outcomes in HIV-controllers were investigated but require further validation.

HIVACAT T-cell immunogen (HTI) is a novel human immunodeficiency virus (HIV) vaccine immunogen designed to elicit cellular immune responses to HIV targets associated with viral control in humans. The AELIX-002 trial was a randomized, placebo-controlled trial to evaluate as a primary objective the safety of a combination of DNA.HTI (D), MVA.HTI (M) and ChAdOx1.HTI (C) vaccines in 45 early-antiretroviral (ART)-treated individuals (44 men, 1 woman; NCT03204617). Secondary objectives included T-cell immunogenicity, the effect on viral rebound and the safety of an antiretroviral treatment interruption (ATI). Adverse events were mostly mild and transient. No related serious adverse events were observed. We show here that HTI vaccines were able to induce strong, polyfunctional and broad CD4 and CD8 T-cell responses. All participants experienced detectable viral rebound during ATI, and resumed ART when plasma HIV-1 viral load reached either >100,000 copies ml −1 , >10,000 copies ml −1 for eight consecutive weeks, or after 24 weeks of ATI. In post-hoc analyses, HTI vaccines were associated with a prolonged time off ART in vaccinees without beneficial HLA (human leukocyte antigen) class I alleles. Plasma viral load at the end of ATI and time off ART positively correlated with vaccine-induced HTI-specific T-cell responses at ART cessation. Despite limited efficacy of the vaccines in preventing viral rebound, their ability to elicit robust T-cell responses towards HTI may be beneficial in combination cure strategies, which are currently being tested in clinical trials.

Background. Treatment with vesatolimod, an investigational, oral, toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a Phase Ib study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with human immunodeficiency virus (HIV)-1. Methods. In this double-blind, multicenter, placebo-controlled trial, participants on antiretroviral therapy with screening plasma HIV-1 RNA levels <50 copies/mL were randomized (6:2) to receive 6-10 doses of vesatolimod (1-12 mg) or matching placebo orally every other week in sequential dose-escalation cohorts. The primary study objectives included establishing the safety and virologic effects of vesatolimod (change from baseline in plasma HIV-1 RNA). Pharmacokinetics and pharmacodynamic/immunologic activity were assessed as secondary objectives. Results. A total of 48 individuals were randomly assigned to vesatolimod (n = 36) or placebo (n = 12). Vesatolimod was generally well tolerated, with no study drug-related serious adverse events or adverse events leading to study drug discontinuation. There were no statistically significant changes from baseline in plasma HIV-1 RNA in the vesatolimod groups, compared to placebo. Vesatolimod plasma exposures increased dose proportionally; consistent responses in cytokines, interferon-stimulated gene expression, and lymphocyte activation were observed with increasing dose levels above 4 mg. Peak elevations 24 hours after receipt of a 6 mg dose were >3.9-fold higher for interferon gamma-induced protein 10 (IP-10), interleukin-1 receptor antagonist (IL-1RA), interferon-inducible T-cell alpha chemoattractant (ITAC) when compared to baseline values. Conclusions. Vesatolimod was well tolerated at doses ranging from 1 to 12 mg. Immune stimulation was observed at doses above 4 mg, providing rationale for future combination trials in people living with HIV.