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

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.

Conflict of interest statement

E.C. is a full-time employee and shareholder of Bristol-Myers Squibb. D. Grasela is a full-time employee and shareholder of Bristol-Myers Squibb. D. Gardiner is a full-time employee and shareholder of GlaxoSmithKline. R.P.B has no competing interests. B.V. is a full-time employee of Bristol-Myers Squibb. A.J.K. is a full-time employee of Bristol-Myers Squibb. I.L. is a stockholder of Bristol-Myers Squibb, which markets ipilimumab for cancer indications The authors confirm that the above disclosures do not alter our adherence to all PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Participant disposition.

Fig 2. HIV-1 RNA change from baseline.

(A) HIV-1 RNA values for individual participants (individual squares arranged vertically represent test results from a given study day for a given participant; the 2 participants with maximum HIV-1 RNA increase and decrease, respectively, are indicated with arrows; the 14 participants with significant increases in HIV-1 RNA are indicated with asterisks; the 2 participants with significant decreases in HIV-1 RNA are indicated with double asterisks); (B) mean HIV-1 RNA values over time for each dose cohort.

Fig 3. Data for the participants with the maximum increase or decrease in HIV-1 RNA from baseline.

(A) Participant A (ipilimumab 1 mg/kg, 2 doses); (B) Participant B (ipilimumab 3 mg/kg, 4 doses).

Fig 4. CD4 count change from baseline.

Individual squares arranged vertically represent test results from a given study day for a given participant.