Randomized, Double‑Blind, Placebo‑Controlled Trial of Long‑Acting bNAbs 10‑1074‑LS and 3BNC117‑LS with Low‑Dose Nivolumab for Durable HIV‑1 Remission during ART Interruption

The primary objective is to assess the impact of combining the two broadly neutralizing antibodies (10‑1074‑LS and 3BNC117‑LS) with low‑dose nivolumab on the ability to maintain immunological control of HIV‑1 during analytical treatment interruption, thereby evaluating a strategy for durable viral remission.

Secondary objectives include:

• Evaluation of the safety and tolerability profile of the investigational medicinal products.
• Determination of the frequency of post‑intervention immunological control of HIV‑1.
• Assessment of the effect on HIV‑1‑specific T‑cell responses following treatment interruption.
• Measurement of changes in the intact HIV‑1 reservoir during and after interruption.
• Characterization of immune‑cell phenotype, activation status, and exhaustion markers.
• Investigation of the influence of autologous antibodies on post‑interventional immunological control.

The trial enrolled 35 adult participants aged 18 to 65 years, including both females and males, who were living with HIV‑1 disease and were receiving stable antiretroviral therapy (ART). Eligible individuals had a documented plasma HIV‑1 RNA level below 50 copies/mL for at least 15 months, a CD4⁺ T‑cell count greater than 500 cells/µL at screening, and were on an integrase inhibitor or boosted protease inhibitor regimen. Participants were required to be negative for hepatitis B and C markers and to have an HIV‑1 reservoir predicted to be sensitive to neutralization by the monoclonal antibody 10‑1074. Lifestyle considerations included mandatory use of barrier contraception for females of reproductive potential and barrier protection for all participants during ART interruption and throughout the 60‑week study period, extending to 15 months after the final infusion. Selection was based on the outlined inclusion criteria, with individuals providing informed consent and meeting the specified virologic, immunologic, and medication stability requirements.

The IDUNN trial is a Phase 4, randomized, double‑blind, placebo‑controlled study evaluating the effect of two long‑acting broadly neutralizing antibodies (10‑1074‑LS and 3BNC117‑LS) combined with low‑dose anti‑PD‑1 (nivolumab) on immunological control of HIV‑1 during antiretroviral therapy (ART) interruption. Participants meeting eligibility criteria are screened, then randomized at the baseline (week 0) visit and receive the first intravenous infusion of study drugs. Subsequent study visits occur at weeks 8 (second infusion), 14, 24, 36, 48 and 60, with each visit including safety assessments, laboratory evaluations, and immunologic monitoring; the week 60 visit serves as the end‑of‑study assessment. The total participant involvement spans approximately 60 weeks plus a follow‑up period of 15 months after the final infusion. The primary endpoint is the time from ART cessation to loss of immunological control, defined by sustained plasma HIV‑1 RNA > 1 000 copies/mL, confirmed CD4⁺ count < 350 cells/µL, or investigator‑determined unacceptable risk. Early termination may occur if the primary endpoint is met, if serious adverse events arise, or if the participant withdraws consent.

The investigational product 3BNC117-LS is supplied as a sterile solution for injection and administered by infusion at a dose of 30 mg/kg. The infusion is given intravenously according to the protocol‑specified schedule, with each dose delivered as a single administration.

The investigational product 10-1074-LS is provided as a sterile solution for injection and administered by infusion at a dose of 10 mg/kg. The infusion is performed intravenously and follows the same dosing intervals as the co‑administered antibody.

The comparator arm receives nivolumab, a low‑dose anti‑PD‑1 monoclonal antibody, supplied for intravenous infusion. The assigned dose is 1 mg/kg administered as a single infusion per dosing visit.

The placebo consists of a 0.9 % sodium chloride solution for intravenous infusion, supplied as a solution for infusion. It is administered at a volume equivalent to 1 mg/kg to maintain blinding, delivered by the same infusion procedure as the active agents.

All study medications are administered in a double‑blind fashion. Dosing occurs on predetermined study days, with each infusion lasting the duration required to achieve the target dose. Participants are monitored for infusion‑related reactions during and after administration. Compliance is assessed by recording the date, time, and administered volume of each infusion in the electronic case report form, and by verifying that the correct product and dose were delivered according to the randomization schedule.

Efficacy is assessed primarily by measuring the time to loss of immunological control after antiretroviral therapy (ART) interruption. Loss of control is defined as any of the following: six consecutive weeks with plasma HIV-1 RNA >1,000 copies/mL or a confirmed level >100,000 copies/mL; two consecutive CD4+ T‑cell counts <350 cells/mm³; participant‑initiated discontinuation; or investigator‑determined unacceptable risk.

Secondary efficacy evaluations are scheduled at weeks 8, 14, 24, 36, 48 and 60, or at the time of ART restart, whichever occurs first. Assessments include:

• Flow cytometry to quantify changes in immune‑cell subsets, activation and exhaustion markers.
• T‑cell ELISpot and lymphocyte proliferation assays to evaluate functional immune responses.
• PCR‑based measurement of intact proviral HIV‑1 DNA per 10⁶ CD4+ T cells.
• Neutralization assays to determine changes in autologous neutralizing antibody activity.
• Additional analysis of the primary endpoint at weeks 24, 36, 48 and 60.