BACKGROUND:HIV-specific broadly neutralising antibodies (bNAbs) can maintain viral control after interrupting antiretroviral therapy (ART). We investigated the duration and efficacy of Fc-engineered long-acting bNAbs (LS-bNAbs) in maintaining ART-free HIV control compared with placebo. METHODS:RIO is a double-blind, randomised, placebo-controlled trial. Eligibile participants were adults age 18-60 years, initiated on ART in early-stage HIV infection, virally suppressed on ART, and had no evidence of viral insensitivity to 10-1074. Participants were randomly assigned (1:1) to receive two LS-bNAbs (3BNC117-LS and 10-1074-LS) in arm A or saline placebo in arm B; participants and study staff were masked to assignment. Eligible participants interrupted ART after receiving blinded intravenous infusions of either bNAbs or placebo. A second optional infusion was offered after 20 weeks for participants who remained virally suppressed without ART. The primary outcome was time to viral rebound 20 weeks after ART interruption, defined as either the first of six consecutive plasma HIV RNA measurements greater than 1000 copies per mL, or two measurements greater than 100 000 copies per mL. All randomly assigned participants were included in the analyses. This study is registered with ClinicalTrials.gov, NCT04319367. FINDINGS:68 participants were randomly assigned, 34 to each arm. By week 20, viral rebound had occurred in eight participants in arm A and 30 in arm B; 75% (95% CI 61-92) of participants in arm A did not have viral rebound, compared with 11% (4-29) of participants in arm B. Participants in arm A were 91% less likely to rebound than were those in arm B (hazard ratio 0·09; 95% CI 0·04-0·21, p<0·0001). There were 326 adverse events in arm A and 260 in arm B, including 19 treatment-related or procedure-related adverse events in arm A and 41 in arm B. Of nine serious adverse events, none were treatment-related. The most commonly reported treatment-related or procedure-related adverse events were fatigue, lethargy, or somnolence: 11 in arm A and nine in arm B. There were two severe adverse events (anal abscesses) possibly related to the study protocol, both in the placebo arm. INTERPRETATION:Long-acting bNAbs can sustain extended ART-free viral control in people treated during early-stage HIV and represent a promising step towards achieving ART-free HIV remission. FUNDING:Gates Foundation.

There is no readily accessible, scalable cure for HIV infection. Trials of HIV-specific broadly neutralising antibodies (bNAbs) demonstrate inhibition of viral replication and reduction of the reservoir of latently-infected cells, potentially offering new strategies for HIV eradication. Animal and human studies suggest bNAbs have multiple activities, including a direct antiviral action and a secondary induction of T cell responses, the 'vaccinal effect'. The RIO trial assessed HIV-specific cell-mediated immunity after dosing with two long-acting bNAbs (10-1074-LS and 3BNC117-LS) in people treated with antiretroviral therapy (ART) since early stage HIV followed by treatment interruption. BNAbs resulted in sustained viral suppression with 75% of participants controlling off ART after 20 weeks. Here we show that HIV-specific T cell immunity was enhanced for at least 36 weeks after bNAbs in aviraemic participants. Gag-specific T cell immune responses predicted virological outcomes. Baseline CD8+ AIM responses predicted longer times to rebound; baseline CD8+ proliferative responses were additionally protective in participants without baseline bNAb resistance mutations. Baseline ELISpot responses were associated with faster rebound. These data highlight the complex interplay between bNAbs and T cells, identify a post-bNAb protective T cell-driven vaccinal effect, and reinforce the role of immune-based interventions as part of HIV cure strategies.

BACKGROUND:Individuals with HIV remain at higher risk of non-communicable diseases associated with interleukin-6-specific (IL-6) inflammation compared to the background population. Despite antiretroviral therapy, some individuals exhibit persistent hyperinflammation. We characterise these understudied longitudinal profiles and distinguish the predictors of chronic versus acute inflammation. METHODS:A subset from the Strategic Timing of Antiretroviral Treatment (START) trial with up to seven years of biomarker follow-up was included. Inflammatory states were defined based on plasma IL-6 levels, measured at randomisation, months eight, 12, and annually until 84. Hyperinflammation was defined as IL-6>1.8 pg/mL; ≥2 consecutive elevated measurements defined persistent hyperinflammation and a single elevated bracketed by non-elevated measurements defined IL-6 blips. Variables associated with these outcomes were analysed by generalized estimating equations. RESULTS:Among 2,102 individuals with a median of 5 (IQR: 4-6) measurements, 861 (41%) had persistent hyperinflammation whereas 575 (27%) had blips. Participants with BMI≥40 versus 18.5 to <25 (OR: 5.49, 95%CI: 4.18-7.20) and females with black ethnicity versus white males (2.58, 2.17-3.06) had increased risk of persistent hyperinflammation but not blips. Other persistent hyperinflammation predictors included higher white blood cell (WBC) counts, HIV-1 RNA, total cholesterol to high-density lipoprotein ratio >5, older age, smoking and diabetes. Of these only higher WBCs were also associated with blips. CONCLUSIONS:Persistent hyperinflammation is strongly associated with demographic characteristics, comorbidities, and HIV-1 RNA, whereas blips were associated with markers of immune activation. Longitudinal IL-6 measurements are needed to distinguish persistent hyperinflammation from blips, which can lead to establishing a "high-risk phenotype" to target for clinical intervention.

Despite the success of antiretroviral therapy, a subset of people with HIV experience low-level viraemia (LLV), a challenging condition with inconsistent definitions and management across settings. We conducted a scoping review of the literature and developed international consensus recommendations through a modified Delphi process involving a multidisciplinary panel of experts. Available evidence shows wide variability in definitions of persistent LLV, most commonly encompassing repeated viral loads between 50 and 1000 copies per mL. Outcomes associated with LLV are heterogeneous. Despite associations between LLV at 50-200 copies per mL and virological failure of more than 1000 copies per mL, resistance emergence or adverse clinical outcomes are inconsistent; stronger evidence links LLV of 200-1000 copies per mL to these endpoints. Based on these findings, we propose a pragmatic management framework that includes prompt confirmation of LLV, assessment of adherence and drug interactions, consideration of resistance testing (especially at viral loads of 200-1000 copies per mL), a broader clinical evaluation, individualised treatment optimisation (according to viral load strata, the genetic barrier to resistance of current and potential antiretroviral regimens, and the HIV resistance profile), and individual prevention strategies for viral loads of 200-1000 copies per mL. This international guidance aims to support clinicians in identifying when LLV requires action, reduce variability in clinical practice, and inform management strategies across diverse health-care settings.

Background:HIV-specific broadly neutralising antibodies (bNAbs) can maintain viral control after interrupting antiretroviral therapy (ART). We investigated the duration and efficacy of Fc-engineered long-acting bNAbs (LS-bNAbs) in maintaining ART-free HIV control compared with placebo. Methods:RIO is a 1:1 randomised double-blind placebo-controlled trial of two LS-bNAbs (3BNC117-LS & 10-1074-LS) in individuals virally suppressed on ART initiated since early-stage HIV. Eligible participants interrupted ART after receiving blinded infusions of either both LS-bNAbs (Arm-A) or placebo (Arm-B). A second optional blinded infusion was offered after 20 weeks for participants who remained virally suppressed without ART. The primary outcome was time to viral rebound 20 weeks after ART interruption, defined as either the first of six consecutive plasma HIV RNA >1,000 copies/mL, or two measurements >100,000 copies/mL. Secondary outcomes included adverse events, long-term viral control and bNAb pharmacokinetics. Findings:Sixty-eight participants were randomised, thirty-four to each arm. By week 20, viral rebound had occurred in 8 Arm-A and 30 Arm-B participants; 75% (95% CI, 61 - 92) of Arm-A participants had not rebounded, compared to 11% (95% CI, 4-29) participants in Arm-B. Arm-A participants were 91% less likely to rebound compared to Arm-B participants (hazard ratio of rebound (HR): 0.09; 95% confidence interval (CI) 0.04 - 0.21, P < 0.001). ART-free viral control using the above endpoints beyond 96 weeks was evident in 7 (25%, 95% CI 13 - 48) Arm-A participants compared to 2 (11%, 95% CI 4 - 29) Arm-B participants (HR: 0.22, 95% CI 0.12 - 0.40, P < 0.001). These seven participants had predicted serum bNAb concentrations below the presumed therapeutic threshold of 10 μg/mL at 96 weeks. Of nine serious adverse events, none were study-related. Conclusion:Long-acting bNAbs can sustain extended ART-free viral control in people treated during early-stage HIV and represent a promising step towards achieving ART-free HIV remission.

RIO is an ongoing double blind randomized placebo controlled human trial in which participants that started antiretroviral therapy (ART) during primary or early-stage infection underwent treatment interruption and were randomly assigned to a group receiving one or two doses of two long acting broadly neutralizing antibodies 3BNC117-LS and 10-1074-LS (Arm A), or saline (Arm B). The two arms differed significantly in time to viral rebound, ART restart and number of individuals that remained off therapy after 96 weeks (p=0.001) 1 . Here we report on the relationship between viremic control, the latent HIV-1 proviral reservoir, rebound viruses and their sensitivity to the infused and autologous antibodies. Pre-infusion reservoir measurements showed low levels of intact proviral HIV-1 DNA in circulating CD4+ T cells in both arms. The rebounding viruses in participants that received the antibodies, showed significant selection for resistance to 10-1074-LS but not to 3BNC117-LS. Notably, there was a significant correlation between initial reservoir sensitivity to autologous antibodies and to 10-1074 and time to rebound. Finally, comparison of pre-infusion and pre-rebound HIV-1 proviral reservoir in participants that received antibodies showed that the reservoir of intact proviruses decayed faster than earlier reports with a half-life of 0.65 years.

BACKGROUND:Definitions of virological failure and treatment discontinuation for long-acting injectable (LAI) cabotegravir and rilpivirine antiretroviral therapy are inconsistent in clinical practice and observational studies, which complicates interpretation and implementation of findings. The CONSENSUS-LAI study aimed to establish consistent definitions of virological failure and treatment discontinuation to enhance evidence transferability and support optimal clinical outcomes. METHODS:The study had two phases. Phase 1 was an international online survey exploring existing definitions of virological and treatment discontinuation, conducted between April 25 and July 1, 2024. Eligible participants were health-care professionals working in infectious disease or sexual health services who had provided care to at least ten people living with HIV in the past 6 months, had prescribed LAI cabotegravir and rilpivirine in clinical trials or clinical practice, and were able to give informed consent. Participants were recruited via social media and mailing lists of medical specialist societies. Phase 2 was a Delphi process, in which a panel of experts, selected to ensure representation from all six WHO regions, scored leading definitions from phase 1 on a 9-point Likert scale. The proposed definitions were scored according to four validity criteria: clarity, usability in the expert's setting, appropriateness across clinical purposes, and applicability across relevant population groups. Revisions were suggested in iterative rounds until consensus was reached. Consensus was predefined as at least 75% of experts agreeing or strongly agreeing (scores 7-9) with the validity criteria. FINDINGS:386 LAI cabotegravir and rilpivirine prescribers across 28 countries completed the survey, revealing 15 definitions for virological failure on LAI cabotegravir and rilpivirine and nine for treatment discontinuation. 52 experts participated in the Delphi process. Consensus agreement on both definitions was reached after two rounds for all validity criteria. For virological failure, the consensus definition was as follows: (a) viral load 200 copies or more per mL or more on two occasions 2-4 weeks apart, or (b) a single viral load of more than 1000 copies per mL, and/or (c) emergent resistance, in the context of timely injections and prior suppression of less than 200 copies per mL, OR (d) unable to suppress viral load to less than 200 copies per mL on continuous therapy. For treatment discontinuation the consensus definition was as follows: people on LAI cabotegravir and rilpivirine who have missed two consecutive injections and have not taken oral bridging in the interim, irrespective of reason for discontinuation. INTERPRETATION:The consensus definitions provide a foundation for aligning practice and evaluating patient outcomes. Further validation of the viral load threshold for virological failure and the optimal viral load retesting window is required. FUNDING:ViiV Healthcare.

INTRODUCTION:Pre- and post-exposure prophylaxis (PrEP and PEP) are important pillars of the HIV prevention portfolio to reduce the risk of acquisition just before or after HIV exposure. While PrEP efficacy has been elucidated in many randomized clinical trials, corresponding data for PEP is extremely difficult to obtain in a controlled setting. Consequently, it is almost impossible to study the impact of PEP initiation delay and duration on HIV risk reduction clinically, which would inform recommendations on PEP use. METHODS:We employ pharmacokinetics, pharmacodynamics and viral dynamics models, along with individual factors, such as drug adherence to investigate the impact of initiation delay and PEP duration on HIV risk reduction. We evaluated PEP using two- and three-drug regimens with a TDF/FTC backbone. Moreover, we study PEP efficacy in the context of PrEP-to-PEP transitions. RESULTS:In our simulations, early initiation of PEP emerged as a pivotal factor for HIV risk reduction. We found that 2-drug (TDF/FTC) PEP may insufficiently protect when initiated > 1 hour post-exposure. When adding a third drug, early initiation was still a critical factor; however, over 90% efficacy could be achieved when PEP was initiated 48 hours post-exposure and taken for at least 14-28 days, depending on the efficacy of the third-drug component. When investigating PrEP-PEP transitions, we observed that preceding PrEP can (1) contribute directly to prophylactic efficacy, and (2) boost subsequent PEP efficacy by delaying initial viral dynamics and building-up drug concentrations, overall facilitating self-managed transitioning between PrEP and PEP. CONCLUSIONS:Our study confirms the critical role of early (< 48 hours) PEP initiation, preferably with three drugs taken for 28 days. Self-start with TDF/FTC and later addition of a third drug is better than not self-starting. Furthermore, our study highlights the synergy between recent PrEP intake and PEP and may help to inform recommendations on PEP use.

The effectiveness of population-level intervention for HIV elimination is influenced by individual-level variation in sexual behaviour. We assess within-person changes in the frequency of condomless anal sex with two or more partners (CLS2+), estimate the transition probabilities and examine the predictors of transitions among a prospective cohort of HIV-negative gay, bisexual, and other men who have sex with men (GBMSM). Participants were recruited through one of three sexual health clinics in London and Brighton (July 2013 to April 2016) and self-completed a baseline paper questionnaire in the clinic. During follow-up, they were invited to complete four-monthly questionnaires twice a year and subsequent annual online questionnaires once a year (March 2015 to March 2018). We used Markov chain models to estimate transition probabilities from 'higher-risk' (CLS2+) to 'lower-risk' (no CLS2+) and vice versa, and to assess factors associated with transitions between different sexual risk levels. Among 1,162 men enrolled in the study, 622 (53.5%) completed at least one online questionnaire. Higher-risk behaviour was reported in 376/622 (60.4%) men during online follow-up. Overall, 1,665/3,277 (37.5%) baseline and follow-up questionnaires reported higher-risk behaviour. More than 60% of men (376/622) reported higher-risk behaviour at least one period during the follow-up, while 39.5% of men (246/622) never reported CLS2+ during the follow-up. In the next four months, the estimated probability of continuing higher-risk behaviour among men who reported higher-risk behaviour was 78%. Calendar time, recent HIV tests, PrEP and PEP use were the predictors of staying in higher-risk behaviour, while less stable housing status was associated with switching to lower-risk behaviour. Among men who reported lower-risk behaviour, the probability of engaging in the same behaviour was 88%. Recent HIV tests, PrEP and PEP use, recreational drugs, chemsex-associated drug and injection drugs, and bacterial STIs diagnosis were the predictors of switching to higher-risk behaviour. Our results indicate that at any one point in time, the majority of GBMSM are at low risk for HIV acquisition, although many experience short periods in which they are at higher risk. Markers of transitions can be utilized to identify which GBMSM are likely to increase or decrease their risk, thus helping the timing of HIV prevention interventions.

Antiretroviral therapy shortages caused by sudden and severe cuts in USAID and PEPFAR have focused attention on strategies to extend antiretroviral supplies and mitigate this crisis. Efficacy data are now available from seven randomized controlled intermittent triple antiretroviral therapy trials. For countries with urgent drug shortages, this evidence supports intermittent dosing 4-5 days-per-week to extend antiretroviral supplies, with clinical benefits for people living with HIV and continued population benefits of minimizing HIV transmission.

Introduction Pre- and post-exposure prophylaxis (PrEP and PEP) are important pillars of the HIV revention portfolio to reduce the risk of infection just before or after HIV exposure. While PrEP efficacy has been elucidated in many randomized clinical trials, corresponding data for PEP is extremely difficult to obtain in a controlled setting. Consequently, it is almost impossible to study the impact of PEP initiation delay and duration on HIV risk reduction clinically, which would inform recommendations on PEP use. Methods We employ pharmacokinetics, pharmacodynamics, and viral dynamics models, along with individual factors, such as drug adherence to investigate the impact of initiation delay and PEP duration on HIV risk reduction. We valuated PEP using two- and three-drug regimens with a FTC/TDF backbone. Moreover, we study PEP efficacy in the context of PrEP-to-PEP transitions. Results In our simulations, early initiation of PEP emerged as a pivotal factor for HIV risk reduction. We found that 2-drug (FTC/TDF) PEP may insufficiently protect when initiated > 1 hour post-exposure. When adding a third drug, early initiation was still a critical factor, however, over 90% efficacy could be achieved when PEP was initiated 48hours post-exposure and taken for at least 14-28days, depending on the efficacy of the third-drug component. When investigating PrEP-PEP transitions, we observed that preceding PrEP can (i) contribute directly to prophylactic efficacy, and (ii) boost subsequent PEP efficacy by delaying initial viral dynamics and building-up drug concentrations, overall facilitating self-managed transitioning between PrEP and PEP. Conclusions Our study confirms the critical role of early (<48hours) PEP initiation, preferably with three drugs taken for 28days. Self-start with TDF/FTC and later addition of a third drug is better than not self-starting. Furthermore, our study highlights the synergy between recent PrEP intake and PEP and may help to inform recommendations on PEP use. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement M.v.K. acknowledges funding from the German ministry for science and education (BMBF), grant number 01KI2016, from the DFG research center MATH+, as well as Sonderforschungsmittel (SoFo) provided through the Robert-Koch Institute. The funders had no role in the design of the study or the decision to publish. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at https://github.com/KleistLab/PEP

Large randomised studies of new long-acting medications for the prevention and treatment of HIV have shown high effectiveness and acceptability. Although modelling studies indicate these agents could be fundamental in HIV elimination, coordination of their entry into health-care markets is crucial, especially in low-income and middle-income countries with high HIV prevalence, where coordination is low despite UNAIDS flagging that global HIV targets will not be met. Research and implementation projects are tightly controlled by originator pharmaceutical companies, with only a small percentage of eligible people living with or affected by HIV benefiting from these projects. WHO, financial donors, manufacturers, and governments need to consider urgent coordinated action from stakeholders worldwide, akin to the successful introduction of dolutegravir into treatment programmes across low-income and middle-income countries. Without this immediate coordination, large-scale access to long-acting agents for HIV will be delayed, potentially extending into the 2030s. This delay is unacceptable considering the established global HIV targets.

This EHA-ESMO Clinical Practice Guideline provides key recommendations for managing HIV-associated lymphomas.The guideline covers clinical, imaging and pathological diagnosis; staging and risk assessment; treatment and follow-up.The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.Recommendations are based on available scientific data and the authors' collective expert opinion.

BACKGROUND For people with HIV and CD4+ counts >500 cells/mm3, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4+ counts are <350 cells/mm3. Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain. METHODS The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4+ counts .500 cells/mm3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021. RESULTS Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4+ count was 648 and 460 cells/mm3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4+ difference was 199 cells/mm3. After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4+ count difference was 155 cells/mm3. After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference). CONCLUSIONS Among adults with CD4+ counts >500 cells/mm3, excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).