An open-label, multiple ascending dose study of the anti-CTLA-4 antibody ipilimumab in viremic HIV patients

PLoS One. 2018 Jun 7;13(6):e0198158. doi: 10.1371/journal.pone.0198158. eCollection 2018.

Abstract

Expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4), a negative regulator of T-cell function, is increased in chronic HIV-1 infection. It was hypothesized that CTLA-4 blockade may enhance immune response to HIV-1 and result in better control of viremia. This open-label, multiple ascending dose study (NCT03407105)-the first to examine ipilimumab in participants with HIV-1 infection-assessed the safety, tolerability, and pharmacokinetics of ipilimumab, as well as whether ipilimumab enhanced immune response to HIV-1 and improved control of viremia. Twenty-four participants received 2 or 4 doses of ipilimumab (0.1, 1, 3, or 5 mg/kg) every 28 days. No serious adverse events (AEs) or dose-limiting toxicities were reported; one participant discontinued ipilimumab for an AE of grade 2 facial palsy. Twenty participants (83.3%) had ≥1 AE; all but 1 were grade 1 or 2. Eight participants (33.3%) had potentially immune-related AEs (7 had grade 1 diarrhea not requiring corticosteroids; 1 who had diarrhea also had transient antinuclear antibody positivity; 1 had grade 2 facial palsy requiring corticosteroids). Two participants (8.3%), one each in the 0.1- and 1-mg/kg dose groups, had a decrease from baseline HIV-1 RNA of 0.85 and 1.36 log10 copies/mL. Fourteen participants (58.3%) had an increase from baseline HIV-1 RNA (mean, 0.87 log10 copies/mL; range, 0.59-1.29). Of these 14 participants, all but 1 were in the higher ipilimumab dose groups (3 or 5 mg/kg). No pattern was noted regarding change from baseline in CD4 or CD8 T cells; ex vivo assessments of immune response were precluded because of inadequate cell viability. Serum concentration data for ipilimumab showed biphasic disposition, with steady state reached by dose 3. Ipilimumab treatment was well tolerated and was associated with variations in HIV-1 RNA in excess of expected repeat measures in most participants, but these were not related to combination antiretroviral therapy status or CD4 counts. The mechanism(s) underlying the increased variation in HIV-1 RNA is unclear and needs further study.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD4 Lymphocyte Count
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / immunology*
  • Dose-Response Relationship, Drug
  • Female
  • HIV Infections / drug therapy*
  • HIV Infections / immunology
  • HIV Infections / metabolism
  • HIV Infections / virology
  • HIV-1 / immunology*
  • Humans
  • Ipilimumab / administration & dosage*
  • Ipilimumab / adverse effects
  • Ipilimumab / pharmacokinetics
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • RNA, Viral / blood
  • Viremia / drug therapy*
  • Viremia / immunology
  • Viremia / metabolism

Substances

  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ipilimumab
  • RNA, Viral

Associated data

  • ClinicalTrials.gov/NCT03407105

Grants and funding

The study sponsor, Medarex (now Bristol-Myers Squibb), was involved in the study design, conduct, and data analysis, supplied study medication, and provided financial support for preparation of the manuscript. The decision to publish was made by the authors. Bristol-Myers Squibb provided support in the form of salaries for those authors who are employees of the company (E.C., D. Grasela, B.V., and A.J.K.). This salary support was not specifically related to this study or preparation of this manuscript. The specific roles of these authors are articulated in the “Author Contributions” section. Professional medical writing and editorial assistance were provided by Matthew Weitz on behalf of inScience Communications, Springer Healthcare (Philadelphia, PA, USA), funded by Bristol-Myers Squibb.