Anti-A4B7 Therapy Defined as Possible HIV Treatment

Saurabh Mehandru, MD

Building on 2004 research that established the human immunodeficiency virus (HIV) depletes CD4+ T cells with A4B7 receptors in the intestines in its earliest disease stages, investigators from the Icahn School of Medicine at Mount Sinai decided to investigate therapeutic options.

Upon their analysis, the team found anti-A4B7 therapy—specifically, vedolizumab (VDZ)—may represent a new therapeutic approach, prompting a couple of ongoing phase 1 clinical trials.

“This study was an extension of our previous work on understanding the role of the immune system within the intestines in patients with HIV infection,” investigator Saurabh Mehandru, MD, told MD Magazine^®. “Additionally, studies from animal models have shown that this drug is promising. Therefore, we wanted to study it in humans.”

Six patients with concomitant HIV—1 infection and irritable bowel disease (IBD) were enrolled in the study; however, 1 patient was excluded from the analyses due to lacking pre-VDZ gut data.

Prior VDZ administration, ileocolonoscopies were performed, and biopsies were collected from the terminal ileum (TI) and the left colon (LC). Following the US Food and Drug Administration’s (FDA’s) approved protocol for IBD, VDZ infusions were administered. Infusions included an induction phase with an infusion of 300 mg intravenous (IV) infusion at weeks 0, 2, and 6. A maintenance phase with an infusion of 300 mg IV every 8 weeks subsequently following the preceding dosing.

Between week 22 and 30 after a treatment, a repeat colonoscopy was performed. Blood was also collected before each infusion, and combination antiretroviral therapy (cART) was administered to participants for the length of the study. As patients continue to be on long-term follow-up, the following data is based on 30 weeks of VDZ therapy.

Among the 5 patients included in the analyses, Mehandru and his team observed safe administration of VDZ and no serious adverse events in treated patients.

Additional observations in patients treated with anti-A4B7 therapy included a significant reduction in B cell subsets within the gastrointestinal (GI) tract; an attrition of lymphoid aggregates within the GI tract; a decrease in naïve CD4⁺T cells in the TI; a decrease in activated CD4⁺T cells in the TI; early changes in natural killer cell composition and activation that equilibrates over time; and a variable effect on stimulated and unstimulated multiply sliced HIV-1 transcripts in blood-derived CD4⁺T cells.

“We noted for the first time that the drug impacts lymphoid aggregates,” Mehandru added. “These aggregates are important for HIV persistence.”

Since lymphoid aggregates function as key “sanctuary sites” for maintaining “viral reservoirs,” the anti-A4B7 therapy’s ability to attenuate them provides important insight regarding HIV-1 therapeutics and eradication efforts. Primarily, anti-A4B7 therapy’s performance in patients with HIV-1 and IBD helps further define a rational basis for its use as a therapeutic option for HIV.

“Next steps are to study this drug with other HIV agents to reduce the reservoir of HIV in the body,” Mehandru said, looking forward. “Additionally, we want to continue to study this drug in patients with inflammatory bowel disease.”

The study authors noted that treatment with anti-A4B7 agents in combination with latency reversal agents (LRAs) may represent a novel therapeutic approach as they have been noted to specifically target the lymphoid aggregates.

The study, “Anti-A4B7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1—infected individuals,” was published online in Science Translational Medicine.