Broadly neutralizing antibodies for HIV therapy in clinical trials: a systematic review

Clinical Snapshot

Key Findings

• P Value: Not reported at the review level; individual trial p-values not synthesised

• Effect Size: Monotherapy: viral load reduction of 0.93–1.8 log₁₀ copies/ml; Combination regimens: up to 2.04 log₁₀ copies/ml reduction. LS-modified bNAbs extended half-life 2- to 5-fold (e.g., VRC01LS: 71 days vs 15 days for parental VRC01)

• Primary Outcome: Antiviral efficacy of bNAbs in HIV-1-infected individuals, measured by viral load reduction and time to viral rebound following treatment

• Nnt Or Sensitivity: Time to viral rebound: monotherapy approximately 4–8 weeks; combination regimens 15–33 weeks. Discontinuation rate due to adverse events: 0.4%. Viremia reduced bNAb half-life by 20–40% relative to suppressed participants

• Confidence Interval: Not reported; no pooled estimates with confidence intervals were calculated in this narrative systematic review

Clinical Application

Currently limited to clinical trial settings. IV administration requires healthcare facility access, limiting real-world scalability. LS-engineering extends dosing intervals (potentially monthly to quarterly), which improves feasibility relative to daily oral ART for selected patients. Resistance-guided patient selection and baseline sensitivity testing add logistical complexity. Cost and manufacturing scalability of bNAbs remain significant barriers to widespread implementation. No bNAbs are currently TGA-approved or PBS-listed for HIV treatment in Australia as of the review period. Australia's HIV epidemic is predominantly clade B, which aligns with the populations studied in most reviewed trials, supporting potential applicability. The RACGP and ASHM guidelines currently recommend standard ART regimens; bNAbs remain investigational. Australian participation in international bNAb trials (e.g., through the Kirby Institute and ASHM-affiliated centres) is ongoing. Long-acting injectable ART (cabotegravir/rilpivirine, PBS-listed from 2023) provides a comparator framework for patient acceptability of non-daily dosing. PBS listing of bNAbs would require Phase III efficacy and cost-effectiveness data not yet available. The low HIV reservoir reduction observed is particularly relevant to Australian functional cure research priorities. Adults with HIV-1 infection who are either viremic with bNAb-sensitive virus or virologically suppressed on ART and seeking long-acting or functional cure strategies. Most applicable to individuals with documented bNAb-sensitive viral strains at baseline, as pre-treatment sensitivity testing appears critical to efficacy.

Abstract

BACKGROUND: Lifelong daily antiretroviral therapy (ART) effectively suppresses human immunodeficiency virus type 1 (HIV-1) replication but does not eradicate the virus, underscoring the urgent need for long-acting antivirals and functional cure strategies. Broadly neutralizing antibodies (bNAbs) have emerged as a promising approach for achieving durable HIV-1 remission. In this systematic review, we summarize recent advances in the development of bNAbs for HIV-1 treatment. METHODS: We searched PubMed, Embase, and Web of Science for clinical trials published up to March 22, 2026. We included data evaluating intravenously administered bNAbs, with or without concomitant conventional ART, and comparing them with placebo, ART or no intervention. These data were used to evaluate the pharmacokinetics, antiviral efficacy, resistance profiles, immunologic effects, and safety of intravenously administered bNAbs. RESULTS: LS-modified bNAbs extended half-life by 2- to 5-fold relative to their parental counterparts (e.g., VRC01LS: 71 vs 15 days), although viremia reduced half-life by 20-40%. In viremic participants harboring bNAb-sensitive virus, monotherapy achieved viral load (VL) reductions of 0.93-1.8 log₁₀ copies/ml, with rebound occurring within approximately 4-8 weeks, whereas combinations regimens achieved declines of up to 2.04 log₁₀ copies/ml and delayed rebound to 15-33 weeks. No consistent reduction in total reservoir size was observed, although early intervention and baseline viral sensitivity appeared to limit reservoir expansion. Resistance emerged through epitope-proximal mutations, with cross-resistance observed mainly among antibodies targeting shared epitope classes. Overall, bNAbs were well tolerated, with rare discontinuations (0.4%) and low immunogenicity. CONCLUSIONS: LS-engineered bNAbs exhibit a longer half-life than their parental antibodies. Combination regimens achieve greater VL reductions and a longer delayed rebound compared with monotherapy, indicating that LS-modified multi-epitope bNAb cocktails are promising for long-acting HIV-1 remission. To become clinically competitive, larger resistance-guided trials are needed to extend dosing intervals, improve resistance mitigation, and define optimal integration with other long-acting therapies.

References

1. 1.Zhao, J., Wu, H., He, J., Luo, Y., & Liu, J. (2026). Broadly neutralizing antibodies for HIV therapy in clinical trials: a systematic review. Infectious Diseases of Poverty. https://doi.org/10.1038/s41579-025-01206-6