Vedolizumab treatment across antiretroviral treatment interruption in chronic HIV infection: the HAVARTI protocol for a pilot dose-ranging clinical trial to assess safety, tolerance, immunological and virological activity

Abstract

Introduction: Continuous antiretroviral therapy (ART) suppresses HIV plasma viral load (pVL) to very low levels, which allows for some immune recovery. Discontinuation of ART leads to pVL rebound from reservoirs of persistence and latency, and progressive immunodeficiency. One promising but controversial strategy targeting CD4⁺ T lymphocytes with a monoclonal antibody (mAb) against α4β7 integrin has shown promise through sustained virological remission of pVL (SVR) in SIV₂₃₉-infected rhesus macaques. We propose to assess the safety and tolerability of vedolizumab, a licensed humanised mAb against human α4β7 integrin, in healthy HIV-infected adults on ART. This study will also assess, by analytical treatment interruption (ATI), whether vedolizumab treatment can induce SVR beyond ART and vedolizumab treatment.

Methods and analysis: The HIV-ART-vedolizumab-ATI (HAVARTI) trial is a single-arm, dose-ranging pilot trial in healthy HIV-positive adult volunteers receiving ART. Twelve consenting persons will be enrolled in sequential groups of 4 to each serial dosing vedolizumab regimen (300 mg, 150 mg, 75 mg). The primary outcomes are: (1) to assess the safety and tolerability of seven serial infusions of vedolizumab at each of three doses; (2) to identify the immunovirological measures, including pVL and T-cell kinetics, that characterise HIV/ART cases before, during, after vedolizumab treatment and ATI; and (3) to seek SVR of pVL after ATI. Secondary outcomes will include immune reconstitution and pVL suppression as well as immune reconstitution and long-term safety following re-initiation of ART in the absence of SVR.

Ethics and dissemination: The study protocol was approved by the Ottawa Health Science Network-REB and by the Health Canada Therapeutic Products Directorate. A Data Safety Monitor will review safety information at regular intervals. The final manuscript will be submitted to an open access journal within a year of study completion.

Trial registration number: ClinicalTrials.gov NCT03147859; https://clinicaltrials.gov/ct2/show/NCT03147859.

Keywords: HIV & AIDS; clinical trials; immunology; inflammatory bowel disease.

Figure 1

Overview of vedolizumab treatment intervention and analytical treatment interruption of antiretroviral therapy (ART). There are three groups of 4 participants each that will be sequentially recruited. Each group will receive 7 infusions of vedolizumab, at weeks 0, 2, 5, 8, 12, 26 and 20. Group 1 will be recruited first and receive 300 mg of vedolizumab per infusion, the highest licensed dose. Group 2 and group 3 will receive 150 mg and 75 mg per infusion, respectively. Screening and baseline will take place approximately 3–6 months apart. Baseline and week 0 assessments can take place at one visit or be split into two visits (ie, the baseline rectal biopsy can take place up to 4 weeks prior to the week 0 visit (or at the same time) when the vedolizumab intervention is started. Participants will start vedolizumab at the week 0 visit, but continue on their pre-study ART regimen until week 6/7 (analytical treatment interruption, ATI). There will be four doses of vedolizumab after ATI at weeks 8, 12, 16 and 20 (each 4 weeks apart from each other). The participant will subsequently visit every 4 weeks until week 52 as per study visit schedule (table 1). ART will be re-initiated prior to week 52 if there is a sustained rebound of plasma viral load as detailed in Methods section.