Summary
A phase II randomized trial found that two long-acting broadly neutralizing antibodies delayed HIV rebound during closely monitored treatment interruption in men who began antiretroviral therapy early. Secondary analyses linked prolonged control to antibody sensitivity, resistance evolution and a reduction in intact proviral reservoir measurements.
A phase II randomized trial has linked two long-acting broadly neutralizing antibodies (bNAbs) with delayed HIV rebound and prolonged periods without antiretroviral therapy (ART) during a closely monitored treatment interruption. Secondary and exploratory analyses of the RIO trial also found that rebounding viruses were frequently resistant to one of the antibodies, while the intact HIV reservoir declined in participants who received the treatment.
The study, published in Nature Medicine, included 68 adult men living with HIV. Participants had started ART during primary or early HIV infection and had maintained viral suppression for at least a year. They were randomly assigned to receive the long-acting antibodies 3BNC117-LS and 10-1074-LS, or saline placebo, two days before stopping ART. The trial was double-blinded and placebo-controlled.
Broadly neutralizing antibodies are designed to recognise parts of HIV that are shared across multiple viral variants. The long-acting LS versions are intended to remain in the circulation for extended periods. ART prevents new rounds of HIV infection but does not remove latent proviruses—viral DNA integrated into the genomes of long-lived CD4+ T cells. These cells form a reservoir that can restart infection when ART is stopped.
Delayed rebound during treatment interruption
The primary clinical outcome of the RIO trial was the time until viral rebound after analytical treatment interruption (ATI). Early rebound, before week 20, occurred in 8 of 34 participants in the antibody arm and 30 of 34 in the placebo arm—75% versus 11%, respectively, with P < 0.001.
The median time to ART restart was 45.4 weeks in the antibody arm, compared with 4.6 weeks in the placebo arm. At 96 weeks, 7 of 29 participants receiving antibodies remained off ART, compared with 2 of 32 in the control group. ART could be restarted because of predefined viral-load or CD4+ T-cell thresholds, clinical symptoms or participant preference, so remaining off treatment was not determined only by viral measurements.
The infusions were generally safe and well tolerated in this study. No study-related serious adverse events were reported; the most common treatment-related events were fatigue, lethargy and somnolence.
The new analyses examined why rebound was delayed in some participants and how the virus changed under antibody pressure. They found strong selection for resistance to 10-1074-LS among rebounding viruses. The geometric mean concentration required to inhibit 80% of test viruses, known as the IC80, rose from 0.09 µg ml−1 for viruses from the initial reservoir to 14.7 µg ml−1 for rebound viruses in the antibody group. Most rebound viruses were completely resistant to 10-1074 in the assay.
Resistance to 3BNC117-LS was much less pronounced. The difference in 3BNC117 sensitivity between reservoir and rebound viruses was not statistically significant, suggesting that the two antibodies exerted different selective pressures during the interruption.
Antibody sensitivity and the HIV reservoir
Participants whose reservoir-derived viruses were more sensitive to their own pre-existing antibodies generally remained off ART for longer in the bNAb arm. Among antibody recipients with measurable autologous neutralizing activity, the mean time to ART restart was 108 weeks, compared with 27.5 weeks among those without it. The association was based on a small subgroup and was correlational, but it suggests that naturally occurring antibodies may complement the infused bNAbs in some people.
The researchers also compared the HIV reservoir before antibody infusion and approximately 52 weeks later. In 22 antibody-treated participants, the intact proviral reservoir—but not the defective reservoir—became significantly smaller, with an estimated half-life of 36 weeks. No measurable reservoir change was observed in 20 control participants. The authors interpret this as suggestive of altered reservoir dynamics under long-acting bNAb exposure in people treated early, rather than as a general estimate for all people living with HIV.
A separate post hoc analysis identified fluctuating viraemia as a common pattern after antibody treatment. Eleven of 29 antibody-arm participants, or 38%, maintained fluctuating HIV RNA levels for 16 to more than 58 weeks without meeting the protocol’s virological criteria for ART restart. Several viruses collected during this period were highly resistant to 10-1074 but retained sensitivity to 3BNC117, indicating that viral control can persist even after partial antibody escape.
The findings apply to a specific group: men who began ART during primary or early HIV infection and were treated at selected clinical research sites in the United Kingdom and Denmark. Reservoir sequencing was unavailable for 33 of the 68 participants, and antibody analyses were limited to people from whom reservoir-derived viruses could be recovered. The study sampled peripheral blood, which may not fully represent tissue reservoirs. The associations between pre-existing antibodies, reservoir decay and delayed rebound therefore help identify possible mechanisms, but do not by themselves establish which mechanism caused prolonged control.
The intervention was tested during supervised ATI with predefined monitoring and ART restart rules. The results support further investigation of long-acting bNAbs and host immunity as tools for controlling HIV after treatment interruption; they do not establish that routine ART can be stopped outside a clinical study.