CROI 2025: Two bNAbs enable viral suppression off-ART in African women in the FRESH cohort

21 March 2025. Related: Conference reports, Cure-related research, .

Simon Collins, HIV i-Base

CROI 2025 included results from a cure-related study using immunotherapy with two bNAbs (VRC07-523LS and CAP256V2LS) and a TLR7 agonist (vesatolimod, GS-9620) in a cohort of 20 African women who started ART in very early acute infection.

Results from this single arm, open-label, phase 2a study were reported in an oral presentation by Thumbi Ndung’u from the Africa Health Research Institute, South Africa.

This is the first HIV cure-related study in South Africa and the first to enrol women with subtype C and in such early HIV infection. Participants were recruited from the FRESH cohort which closely monitored women who had high risks associated with HIV and which included HIV testing every two weeks. The cohort also involves starting ART on first diagnosis when most women were only in Fiebig stage 1.

Enrolment criteria for this study included being suppressed on ART for at least 12 months, having a current CD4 count >500 cells/mm3 and being sensitive to at least one of the two bNAbs.

Oral vesatolimod was given at baseline and every two weeks up to week 18. A single IV infusion of both bNAbs were given at week 1 and ART was interrupted at week 7, remaining off-ART for 48 weeks unless criteria to restart ART were met. Restart criteria included viral load >1000 copies/mL for 8 weeks, confirmed >100,000 copies/mL or confirmed CD4 count <350 cells/mm3.

Baseline characteristics included median CD4 count 880 cells/mm3 (IQR: 520 to 1472) and median time on ART 6.9 years (IQR: 1.7 to 8.5). ART had been started a median of 1 day after HIV diagnosis (IQR: 0 to 3) before seroconversion when viral load was still low and when western blot was still negative. At baseline, 11/20 women were sensitive to both bNAbs, with 7/20 only sensitive to VRC07 and 2/10 only sensitive to CAP256.

At week 20, mean plasma levels of both bNAbs remained above the therapeutic doses of 100 x median IC50 levels of 9 ug/mL and 0.32 ug/mL for VRC07 and CAP246, but dropped below these levels at weeks 24 and 32 respectively.

The median time to viral rebound >50 copies/mL was 11 weeks (95%CI: 7 to 18). Although 12/20 showed typical viral load dynamics, 8/20 participants reported suppressed or fluctuating viral load, with some women resuppressing from levels of about 100,000 copies/mL without ART.

Three different responses were reported: early viral rebound within the first 8 weeks of the ATI in 35% (n=7/20), delayed viral rebound in 35% (7/20) who restarted from weeks 16 to 24 and 30% (n=6/20) who remained off-ART at week 48, 4 of whom are still off-ART after a median of 1.5 years (range: 1.2 to 2.4).

Tolerability was generally good, as most participants reported mild infusion-related reactions. One early withdrawal was linked to a mild cytokine reaction to vesatolimod.

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These results are important for showing a potential vaccinal effect from bNAbs, with viral resuppression in 4/20 cases without ART and sometimes from high viral load levels.

Although this is a single arm study without a control arm, the percentage of such responders is perhaps higher than would be expected from post-treatment controllers, although such early use of treatment also makes this aspect of the results difficult to interpret. A control arm was not included because this was primarily a safety rather than efficacy study.

The results are similar to those reported in the RIO study which was presented in the same session at CROI.

As with the RIO study, a significant number of participants rebounded to much higher levels than was planned in the study protocol and referred to in the participant information used for informed consent.

This supports the importance of establishing retrospective and prospective longer-term safety registries for participants in studies that include an ATI. This should also include the time to resuppression after ART is restarted, which wasn’t reported for the FRESH participants.

It is unclear whether vesatolimod contributed to these results, as previous studies have only suggested a possible modest impact on the viral reservoir.

References

  1. Ndung’u T et al for the FRESH study. Evaluation of 2 bNAbs Plus Vesatolimod in Early-Treated South African Women With HIV-1 During ATI. CROI 2025. Oral abstract 105.
    www.croiconference.org/abstract/2240-2025 (abstract)
    watch.croiwebcasts.org/2025croi/ap/54100 (webcast)
  2. ROI 2025: RIO study: Dual-bNABs keep viral load undetectable off-ART – plus a potential first case of vaccine-like HIV remission. HTB (March 2025).
    https://i-base.info/htb/50530
  3. 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.
    www.croiconference.org/abstract/3760-2025 (abstract)
    watch.croiwebcasts.org/2025croi/ap/54102 (webcast)
  4. SenGupta D et al. The TLR7 agonist vesatolimod induced a modest delay in viral rebound in HIV controllers after cessation of antiretroviral therapy. Sci Transl Med. 2021 Jun 23;13(599):eabg3071. doi: 10.1126/scitranslmed.abg3071.
    pubmed.ncbi.nlm.nih.gov/34162752
  5. Rasmussen TA, Lewin SR. Toll-like Receptor 7 Agonists in People Living With HIV: Implications for Immunotherapeutic Strategies for an HIV Cure. Clin Infect Dis. 2021 Jun 1;72(11):e825-e827. doi: 10.1093/cid/ciaa1539.
    pubmed.ncbi.nlm.nih.gov/33044543

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