RIO study: Dual-bNABs keep viral load undetectable off-ART – plus a potential first case of vaccine-like HIV remission

12 March 2025. Related: Early access, Conference reports, Cure-related research, .

Simon Collins, HIV i-Base

The first results from the UK RIO study were presented at CROI 2025  in an oral abstract session focussed on cure-related research by Professor Sarah Fidler from Imperial College London. [1]

Additional results, including a potential vaccine-like cure were presented in posters by Professor John Frater and Dr Mohammed Altaf from the University of Oxford. [2, 3]

RIO is a randomised (1:1) placebo-controlled study looking at whether participants receiving two LS-bNABs (Arm A) could maintain viral load suppression off-ART during an analytic treatment interruption (ATI), for longer than participants who received a placebo (Arm B). Criteria to restart ART during the ATI included viral load >1000 copies/mL for six weeks or confirmed >100,000 copies/mL. The primary outcome included the time to loss of viral suppression up to week 20.

Entry criteria included being currently suppressed on ART for at least 12 months and initially having started ART during early HIV infection. The two long acting bNAbs were 3BNC117-LS & 10-1074-LS and included baseline screening for 10-1074. The study also included the option of a second set of bNAb infusions for participants in Arm A and open-label bNAbs for participants in Arm B after ART was restarted following the initial ATI.

Of the 68 participants enrolled (145 were screened), 63/68 were predicted to be sensitive to 10-1074 at baseline and 5/68 failed to amplify.

By week 20, significantly few participants had not rebounded in the active arm: 25/68 vs 3/34 in Arms A vs B, respectively. By week 20, Arm A participants were 91% less likely to rebound compared to Arm B (HR: 0.09; 95% CI: 0.04, 0.21, p<0.0001). Additionally, viral load continued to be suppressed during the ATI in 13/34 and 7/34 participants in Arm A out to 48 weeks and 72 weeks respectively, compared to 2/34 and 2/34 in Arm B.

Modelled bNAbs plasma levels remained above the minimum active target of 10μg/mL for 48 weeks after last bNAb dose, for 10-1074-LS and 3BNC117-LS respectively. Six participants in Arm A remained virally suppressed off ART more than 48 weeks after the last bNAb dose. HIV Gag-specific T-cell responses were enhanced following bNAb dosing in those remaining suppressed, consistent with a vaccine-like response.

Also important, two participants in the placebo arm also remained undetectable for more than a year, showing post-treatment control without receiving bNAbs. This shows the important of randomised studies with control arms in cure-related research.

The safety results included a lack of serious events with all of the nine SAEs, including one death, judged unrelated to study drugs, ATI or protocol.

The two posters, presented by Professor John Frater and Mohammed Altaf, both from Oxford University, expanded on the immune responses generated by the bNAbs. [2, 3]

Although previous studies have shown that bNAbs can sustain viral suppression, this is the first study to show a post-bNAbs vaccine-like immune response. People who received bNABs developed stronger immune activation markers compared to participants receiving the placebo and that these enhanced immune responses against HIV were associated with greater viral load suppression.

These results included one participant who experienced viral load rebound during an ATI but not sufficiently high to meet the criteria to restart ART. Instead, viral load spontaneously resuppressed to undetectable levels and viral suppression has now been maintained for more than 18 months off-ART.

This case is a 38-year-old man in Arm B who had seroconverted in 2017 with viral load of 55,000 copies/mL before starting ART within three weeks. During the initial ATI, viral load rebounded to 6225 copies/mL after 4 weeks off-ART. He then received dual bNAbs and restarted ART for 6 months before a second ATI. This time viral load rebounded after five weeks and remained detectable for 20 weeks but to lower levels (peak 1893 copies/mL).

Viral load then spontaneously became undetectable  to <20 copies/mL and remained this low for 80 weeks. During this time, PK levels of both bNAbs were <10ug/mL and ART was undetectable in plasma.

Although HIV in this participant was sensitive to 10-1074 at baseline it was 100% resistant during the second ATI with IC80 >50ug/mL. New HIV-specific immune responses were detected during the second ATI. The HIV viral reservoir also decreased from 2.1 intact proviral DNA copies/million CD4 T cells at baseline to to 0.58 copies/mL at week 37 after the second ATI.

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The oral presentation and conference included a thank-you to all participants. This study included significant commitment for study visit and the impact of undertaking one or more ATIs and the uncertainty of these periods off-ART. This including several people experienced viral load rebound to higher than  1 million/copies/mL due to extremely rapid rebound while waiting for confirmation of viral load >100,000 copies/mL.

This concern led to Ming Lee and other RIO researchers looking at viral load responses is similar studies. The results will hopefully coordinate closer collaborations between different cure-related research groups, more comprehensive reporting, and hopefully both retrospective and prospective safety registries for studies involving an ATI. [5]

These exciting early results are the first randomised placebo-controlled data showing a significant impact of bNAbs on maintaining viral load for more than a year in some participants and a possible case where this vaccine-like effect might generate HIV remission. The next steps in analyses that are already ongoing is to try to understand why only some participants experience such potent and durable responses. 

10-1074 and 3BNC-117 were developed by Professor Michel Nussenzweig at Rockefeller University and are now licensed for further development to Gilead as teropavimab and zinlirvimab (TAB and ZAB). Although bNAbs are generally developed as highly priced drugs for high-income countries, Dr Nussensweig has previously said that with economies of scale and high global demand the price could potentially be less than $200-300, and that future bNAbs could be even stronger and more potent.

The press conference that discussed the RIO study is online and open access. [5]

Simon Collins is a community representative on the RIO study,

References

Unless stated otherwise, all references are to the Programme and Abstracts of the Conference on Retroviruses and Opportunistic Infections, 9 to 12 March 2025.

  1. Fidler S et al for the RIO Trial Investigators. RIO: A Randomised Placebo-Controlled Study of 2 LS-bNAbs in People Treated in Early HIV. CROI 2025. Late-breaking oral abstract 107.
  2. John Frater et al for the RIO Trial Investigators. Sustained Post-Rebound HIV Remission With Enhanced T-Cell Immunity After LS-bNAbs: A Case Report. CROI 2025. Poster abstract 505.
  3. Altaf M et al for the RIO Trial Investigators. Sustained T Cell–Mediated Immunity After LS-bNAbs in the RIO Trial: A Vaccinal Effect. CROI 2025. Poster abstract 506.
  4. Lee MJ et al. The impact of analytical treatment interruptions and trial interventions on time to viral re-suppression in people living with HIV restarting ART in cure-related clinical studies: a systematic review and meta-analysis. J Int AIDS Soc. 2024 Aug;27(8):e26349. doi: 10.1002/jia2.26349.
    https://pmc.ncbi.nlm.nih.gov/articles/PMC11330850/
  5. CROI 2025 Monday (March 10) Press Conference.
    https://www.youtube.com/watch?v=QnFbmQ1GelM

Links to other websites are current at date of posting but not maintained.