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Background: Ibalizumab (IBA) is a humanized monoclonal antibody that binds CD4 domain 2 and blocks HIV-1 entry. TMB-202 was a Phase IIb clinical trial investigating the safety, efficacy and tolerability of IBA administered by intravenous (IV) infusion every 2 or 4 weeks in patients with triple-class resistant HIV-1 infections. Viral resistance testing was performed to assess the activity of IBA against multi-drug resistant (MDR) HIV.
Methods: 113 patients with MDR HIV were treated with IV IBA in combination with an optimized background regimen. Baseline resistance test results for n=105 patients were evaluated to assess the IBA susceptibility of MDR HIV and of HIV with reduced susceptibility to the approved HIV entry inhibitors enfuvirtide (ENF) and maraviroc (MVC). IBA susceptibility was determined by maximum percent inhibition (MPI) and ICHALFMAX Fold Change (ICHMFC) in the PhenoSense HIV Entry assay (Monogram Biosciences).
Results: There was no significant difference in IBA MPI or ICHMFC between patient HIV isolates with wild-type susceptibility to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), or protease inhibitors (PIs) (median MPI = 98%, 96%, and 97%, respectively; median ICHMFC = 1.1, 1.1, and 1.0, respectively) and isolates that were resistant to all NRTIs, NNRTIs, or PIs (median MPI = 99%, 99%, and 97%, respectively; median ICHMFC = 1.0, 1.0, and 0.9, respectively). No difference in IBA susceptibility between patient HIV isolates with wild-type susceptibility to integrase inhibitors (INSTIs) (median MPI = 97%; median ICHMFC = 0.9) and those with resistance to INSTIs (median MPI = 95%; median ICHMFC = 0.9) was observed (n=17). IBA susceptibility was similar for patient isolates with wild-type susceptibility to ENF (median MPI = 96%, median ICHMFC = 1.0) and for those with reduced susceptibility to ENF (median MPI = 94%, median ICHMFC = 1.0). IBA susceptibility was similar for patient isolates with wild-type susceptibility to the coreceptor antagonist MVC (median MPI = 99%, median ICHMFC = 1.0) and for those with reduced susceptibility to MVC (median MPI = 98%, median ICHMFC = 0.8).
Conclusions: Ibalizumab is effective despite resistance to all other antiretrovirals. Ibalizumab is a potent new tool for treatment of MDR HIV.