Impact of Anti-PD-1 and Anti-CTLA-4 on the Human Immunodeficiency Virus (HIV) Reservoir in People Living With HIV With Cancer on Antiretroviral Therapy: The AIDS Malignancy Consortium 095 Study

Abstract

Background: Antibodies to programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) may perturb human immunodeficiency virus (HIV) persistence during antiretroviral therapy (ART) by reversing HIV latency and/or boosting HIV-specific immunity, leading to clearance of infected cells. We tested this hypothesis in a clinical trial of anti-PD-1 alone or in combination with anti-CTLA-4 in people living with HIV (PLWH) and cancer.

Methods: This was a substudy of the AIDS Malignancy Consortium 095 Study. ART-suppressed PLWH with advanced malignancies were assigned to nivolumab (anti-PD-1) with or without ipilimumab (anti-CTLA-4). In samples obtained preinfusion and 1 and 7 days after the first and fourth doses of immune checkpoint blockade (ICB), we quantified cell-associated unspliced (CA-US) HIV RNA and HIV DNA. Plasma HIV RNA was quantified during the first treatment cycle. Quantitative viral outgrowth assay (QVOA) to estimate the frequency of replication-competent HIV was performed before and after ICB for participants with samples available.

Results: Of 40 participants, 33 received nivolumab and 7 nivolumab plus ipilimumab. Whereas CA-US HIV RNA did not change with nivolumab monotherapy, we detected a median 1.44-fold increase (interquartile range, 1.16-1.89) after the first dose of nivolumab and ipilimumab combination therapy (P = .031). There was no decrease in the frequency of cells containing replication-competent HIV, but in the 2 individuals on combination ICB for whom we had longitudinal QVOA, we detected decreases of 97% and 64% compared to baseline.

Conclusions: Anti-PD-1 alone showed no effect on HIV latency or the latent HIV reservoir, but the combination of anti-PD-1 and anti-CTL-4 induced a modest increase in CA-US HIV RNA and may potentially eliminate cells containing replication-competent HIV.

Clinical trials registration: NCT02408861.

Keywords: HIV; HIV latency; anti–CTLA-4; anti–PD-1.

Figure 1.

Study profile. *Excludes pancreas, prostate and microsatellite stable colorectal cancers. Abbreviations: Ipi, ipilimumab; KS, Kaposi sarcoma; MTD, maximal tolerated dose; Nivo, nivolumab.

Figure 2.

Cell-associated unspliced human immunodeficiency virus (HIV) RNA during immune checkpoint blockade (ICB). The level of cell-associated unspliced HIV RNA during ICB shown in absolute numbers and as fold-changes from baseline for the entire cohort (A and B) and for groups receiving nivolumab alone (C) or nivolumab plus ipilimumab (D). Data points are connected for the same participant receiving nivolumab plus ipilimumab in cycle 1 (E) and cycle 4 (F). G, Fold-changes from baseline are displayed and compared across groups receiving nivolumab or nivolumab plus ipilimumab. Abbreviations: CA-US, cell-associated unspliced; FC, fold-change; HIV, human immunodeficiency virus; ICB, immune checkpoint blockade; Ipi, ipilimumab; Nivo, nivolumab.

Figure 3.

Plasma human immunodeficiency virus (HIV) RNA during immune checkpoint blockade (ICB). Plasma HIV RNA prior to and following the ICB in cycle 1 is shown in absolute numbers and as fold-change from baseline for the entire cohort (A and B) and for groups receiving nivolumab monotherapy (C) or combination therapy with nivolumab plus ipilimumab (D). Abbreviations: FC, fold-change; HIV, human immunodeficiency virus; ICB, immune checkpoint blockade; Ipi, ipilimumab; Nivo, nivolumab.

Figure 4.

Effects on the frequency of human immunodeficiency virus (HIV)–infected cells. The level of cell-associated total HIV DNA during immune checkpoint blockade in cycles 1 and 4 is shown in absolute numbers for the entire cohort (A). The frequency of cells containing replication-competent HIV measured by a quantitative viral outgrowth assay and expressed as infectious units per million shown for the entire cohort (B) and for groups receiving nivolumab alone (C) or nivolumab plus ipilimumab (D). Abbreviations: FC, fold-change; HIV, human immunodeficiency virus; ICB, immune checkpoint blockade; Ipi, ipilimumab; LOQ, limit of quantification; Nivo, nivolumab.