VITN Blog #2: Ibalizumab as an antiretroviral agent for HIV-1

As we heard from Dr. David Katzenstein and Caroline Maposhere today, therapy using multiple antiretroviral drugs has proven tremendously successful in the suppression of HIV viral infection in millions worldwide. However, some patients are infected with multidrug-resistant (MDR) HIV. They have demonstrated lack of response to drugs in several classes, such as nucleoside reverse-transcriptase inhibitors, protease inhibitors, integrase inhibitors, and fusion inhibitors. As a result, their clinical outcomes are substantially poorer than those of patients with HIV strains susceptible to typical treatments.

This study evaluates the antiretroviral activity of the monoclonal antibody ibalizumab in a phase 3 clinical trial designed in collaboration with the FDA, which has designated ibalizumab an orphan drug. This designation is intended for treatments of diseases affecting less than 200,000 people in the United States and that might not otherwise be developed without the support of the FDA. MDR HIV-1 falls in this category and has actually become less common over the past several decades, but orphan drugs like ibalizumab may offer hope to patients who have tried traditional therapies to no avail.

HIV-1 infects and kills T cells positive for the surface glycoprotein CD4. A glycoprotein on the HIV-1 envelope surface, gp120, is crucial for binding of the virus to CD4 and subsequent entry into the cell. Ibalizumab is a monoclonal antibody, which means that it is produced by cells that are clones of one another and has specificity to a single antigen. Ibalizumab’s antigen is CD4, and it binds to a particular region within the receptor called extracellular domain 2. This binding of ibalizumab to CD4 on T cells prevents gp120 from facilitating entry of the virus into those same T cells. HIV-1 cannot replicate without a host cell, so it is effectively blocked from perpetuating itself. Given this strategy, ibalizumab would best be classified as a fusion inhibitor.

The authors of the study enrolled only those HIV-1 patients who were resistant to at least one drug in at least three classes (you might imagine that these individuals would be willing to use an orphan drug as a last resort; in fact, 5 enrollees were resistant to all drugs currently available for HIV-1 treatment). The results were encouraging; addition of ibalizumab to a pre-existing drug regimen decreased viral load and increased CD4+ T cell count. Reduced susceptibility to ibalizumab due to genetic modification of HIV-1 gp120 was unfortunately observed in some patients. For people facing the prospect of end-stage AIDS, though, even modest improvement can be meaningful.

Study: “Phase 3 Study of Ibalizumab for Multidrug-Resistant HIV-1” (https://www.nejm.org/doi/full/10.1056/NEJMoa1711460)

Article: “An option for treatment of multidrug-resistant HIV” (https://www.nature.com/articles/s41591-018-0191-7)

- Panos Vandris