How a Novel Monoclonal Antibody Is Winning Against Multidrug-Resistant HIV
Imagine having an enemy that constantly changes its disguise, evading every defense you throw at it. For approximately 25,000 people in the United States living with multidrug-resistant HIV, this isn't a hypothetical scenario—it's their daily reality 3 . These individuals face a virus that has outsmarted most available medications, leaving them with dwindling treatment options and uncertain futures.
The story of HIV treatment has been one of remarkable scientific achievement, transforming what was once a fatal diagnosis into a manageable chronic condition for many. Yet beneath this success lies a persistent challenge: drug resistance.
When HIV replicates in the body, it constantly mutates. Some of these random mutations accidentally equip the virus with the ability to resist antiretroviral drugs. As people with HIV live longer and undergo multiple treatment regimens, a subset eventually develops resistance to drugs across different classes, creating multidrug-resistant (MDR) HIV-1 3 .
Traditional HIV drugs are small molecules that target specific viral proteins inside infected cells. Ibalizumab represents a fundamentally different strategy. As a monoclonal antibody, it's a large, complex protein designed to mimic our natural immune defenses. Specifically, ibalizumab is a recombinant humanized immunoglobulin G4 (IgG4) monoclonal antibody that targets the CD4 receptor on human immune cells—HIV's primary entry point 3 9 .
This approach is like changing the locks instead of fighting the burglar once they're already inside.
HIV typically infects cells by having its gp120 protein bind to domain 1 of the CD4 receptor 3
This binding induces steric hindrance—a physical blocking that prevents shape changes 9
HIV cannot complete its entry process, even though it remains attached to the cell 3
Unlike earlier antibodies that targeted the virus itself, ibalizumab temporarily modifies the host's immune cells to make them resistant to HIV infection. Crucially, because it binds away from the MHC-II binding site, it does not suppress normal immune function 5 . This mechanism works against both CCR5- and CXCR4-tropic strains of HIV, covering a broad spectrum of the virus 9 .
The dosing regimen—an initial 2000 mg loading dose followed by 800 mg maintenance doses every 14 days—maintains sufficient drug levels to continuously block enough CD4 receptors and prevent viral escape 9 .
Unlike immunosuppressive therapies, ibalizumab preserves normal immune function while blocking HIV entry, making it a unique therapeutic approach with a favorable safety profile 5 .
While ibalizumab demonstrated efficacy in controlled clinical trials, these typically involve carefully selected participants under ideal conditions. The PROMISE-US study (Prospective Observational Study of Multidrug-Resistant Patient Outcomes with and without Ibalizumab in a Real-World Setting: United States) takes a different approach—it examines how the drug performs in everyday clinical practice 1 2 .
This phase 4, multicenter study, identified clinically as NCT05388474, represents the first real-world registry specifically designed to capture long-term outcomes for heavily treatment-experienced patients with multidrug-resistant HIV-1 2 . Led by researchers including Dr. Charlotte-Paige Rolle, the study aims to fill critical knowledge gaps about factors that impact long-term virologic control in this challenging population 2 .
PROMISE-US employs a retrospective and prospective, observational, non-interventional design, collecting data from patients' medical records without altering their treatment plans 1 . This "real-world" approach provides insights that complement findings from traditional randomized controlled trials.
| Aspect | Description |
|---|---|
| Study Type | Phase 4, observational, non-interventional |
| Participants | Heavily treatment-experienced adults with multidrug-resistant HIV-1 |
| Sample Size | 114 patients enrolled as of November 2023 1 |
| Cohorts | C1: 70 patients not receiving ibalizumab; C2: 44 patients receiving ibalizumab |
| Data Collection | Retrospective and prospective, using medical records |
| Primary Outcome | Long-term efficacy and durability of ibalizumab-based regimens |
Patients receiving ibalizumab as part of their antiretroviral regimen
patients
Matched patients not receiving ibalizumab
patients
As of November 2023, the PROMISE-US study had enrolled 114 participants—70 in the non-ibalizumab cohort (C1) and 44 in the ibalizumab cohort (C2) 1 . The baseline data revealed fascinating patterns in how clinicians select treatments for this complex population.
The two cohorts were well-matched in terms of demographic characteristics including race, ethnicity, sex, gender, and time since HIV diagnosis 1 . However, significant differences emerged in disease severity indicators, providing insight into real-world treatment decisions.
The data clearly showed that ibalizumab was more frequently selected for patients with more advanced HIV disease. Specifically, those receiving ibalizumab had:
| Characteristic | Cohort 1 (Non-ibalizumab) | Cohort 2 (Ibalizumab) | Significance |
|---|---|---|---|
| Sample Size | 70 patients | 44 patients | - |
| Demographics | Well-matched | Well-matched | Not significant |
| HIV Viral Load | Lower | Higher | p = 0.0629 |
| CD4 T-cell Count | Higher | Lower | p = 0.0001 |
| CD4 <200 among viremic | 26% | 56% | p = 0.0376 |
| Prior ibalizumab exposure | None | 80% >12 months | - |
This treatment selection pattern makes intuitive sense—clinicians typically reserve the newest therapeutic options for their most challenging cases. The subset of patients receiving both ibalizumab and the newer capsid inhibitor lenacapavir displayed the most advanced disease, with the highest viral loads and lowest CD4 counts of all participants, though this group was small (n=12) 2 .
By March 2025, the PROMISE-US investigators had analyzed enough follow-up data to present interim efficacy results at the Conference on Retroviruses and Opportunistic Infections (CROI). The findings were striking, especially considering the more advanced disease in the ibalizumab group .
Among patients with detectable viral load at baseline (defined as >50 RNA copies/mL), similar proportions achieved undetectable levels regardless of treatment group:
of C1 vs.
of C2 achieved undetectable viral load
(p=0.873)
of C1 vs.
of C2 achieved undetectable viral load
(p=0.524)
The statistical non-significance of these differences is actually clinically remarkable—despite starting with more severe disease, the ibalizumab group achieved similar virologic suppression rates as the less advanced control group.
The real-world safety profile of ibalizumab aligned with earlier clinical trials. The drug was well-tolerated with no infusion reactions reported and no treatment discontinuations in the ibalizumab group due to adverse events . This favorable safety profile is particularly important for a medication intended for long-term use in a chronically ill population.
Durability data was equally encouraging—80% of participants in the ibalizumab group had remained on the therapy for greater than 12 months, demonstrating its viability as a long-term treatment option 1 . Additionally, research from the TMB-311 expanded access study showed that ibalizumab-naïve patients receiving the drug experienced notable and early viral load reductions with sustained increases in CD4+ cell counts over 24 weeks 6 .
| Patient Group | Viral Load <50 copies/mL at Baseline | Viral Load <50 copies/mL at Week 24 | CD4+ Cell Count Change |
|---|---|---|---|
| Prior ibalizumab exposure | 59% (23/39) | 76% (26/34) | Increased |
| Ibalizumab-naïve | 0% (0/38) | 46% (11/24) | Increased |
The promising results from PROMISE-US and other ibalizumab studies point toward a future where multidrug-resistant HIV becomes increasingly manageable. Researchers are particularly excited about combining ibalizumab with other novel agents like lenacapavir, which showed enhanced activity in the sickest patient subset 2 .
Christian Marsolais, Ph.D., Senior Vice President and Chief Medical Officer of Theratechnologies, notes: "We continue to analyze data from PROMISE-US to understand the long-term safety and efficacy of ibalizumab, particularly with regard to its suitability for combination with long-term injectable therapies" 2 .
This combination approach leverages multiple mechanisms of action to create a therapeutic "wall" that the virus struggles to overcome, even when it develops resistance to one component.
Despite these advances, challenges remain. The intravenous administration every 14 days presents logistical hurdles compared to oral medications, though the recent FDA approval for intravenous push administration has reduced infusion time from 15 minutes to just 30 seconds 7 . Additionally, as with all HIV therapies, resistance to ibalizumab can emerge through mutations in the V5 loop of gp120, though this appears relatively uncommon in clinical practice 3 .
Case reports of hepatitis B reactivation in one patient receiving ibalizumab highlight the importance of vigilance for unexpected adverse effects, particularly as these therapies move into broader use 5 .
The story of ibalizumab and the PROMISE-US study represents more than just another treatment option—it symbolizes a fundamental shift in our approach to therapeutic innovation. By specifically designing treatments for the most challenging cases and studying them in real-world settings, researchers are ensuring that progress in HIV treatment reaches even those who had nearly exhausted their options.
As Dr. Smitha Gudipati, an infectious disease specialist presenting the recent PROMISE-US findings at CROI, stated: "We are encouraged to see such impressive reductions in viremia in patients whose regimens include ibalizumab, despite having lower CD4 counts and higher viral loads at baseline than the non-ibalizumab control group" .
For the thousands of people living with multidrug-resistant HIV, this research represents more than just data points—it represents renewed hope for a future where their virus remains suppressed, their immune systems stay strong, and they can live full lives unburdened by the fear of running out of options.