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

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....

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Published in:Clinical infectious diseases 2021-10, Vol.73 (7), p.e1973-e1981
Main Authors: Rasmussen, Thomas A, Rajdev, Lakshmi, Rhodes, Ajantha, Dantanarayana, Ashanti, Tennakoon, Surekha, Chea, Socheata, Spelman, Tim, Lensing, Shelly, Rutishauser, Rachel, Bakkour, Sonia, Busch, Michael, Siliciano, Janet D, Siliciano, Robert F, Einstein, Mark H, Dittmer, Dirk P, Chiao, Elizabeth, Deeks, Steven G, Durand, Christine, Lewin, Sharon R
Format: Article
Language:English
Subjects:
Acquired Immunodeficiency Syndrome
CTLA-4 Antigen
HIV Infections - complications
HIV Infections - drug therapy
HIV-1
Humans
Neoplasms
Online Only
Programmed Cell Death 1 Receptor
Virus Latency
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Summary: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. 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. 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. 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. NCT02408861.
ISSN:1058-4838
1537-6591
DOI:10.1093/cid/ciaa1530