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 PD-1 and CTLA-4 may perturb 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 pre-infusion and one and seven days after the first and fourth dose 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 forty participants, 33 received nivolumab and seven nivolumab plus ipilimumab. Whereas CA-US HIV RNA did not change with nivolumab monotherapy, we detected a median 1.44 fold-increase (IQR 1.16–1.89) after the first dose of nivolumab and ipilimumab combination therapy (P=0.031). There was no decrease in the frequency of cells containing replication-competent HIV, but in the two individuals on combination ICB for whom we had longitudinal QVOA, we detected decreases of 97% and 64% compared to baseline. Conclusion 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.

Combination Immune Checkpoint Blockade Enhances IL-2 and CD107a Production from HIV-Specific T Cells Ex Vivo in People Living with HIV on Antiretroviral Therapy

“…Other small case series or case reports in PWH on ART with concomitant malignancy have similarly shown an increase in HIV-specific CD4 1 and CD8 1 T cells in some but not all participants following antiPD-1 treatment (16,17). There are currently seven clinical trials of antiPD-1 enrolling PWH on ART, including three studies enrolling people without cancer (https://clinicaltrials.gov) and one study evaluating the impact of antiPD-1 and antiCTLA-4 (18).…”

Knowledge From London and Berlin: Finding Threads to a Functional HIV Cure

“…Additionally, in a new clinical trial (ClinicalTrials.gov Identifier: NCT02408861), participants with HIV associated classical Hodgkin lymphoma or solid tumors received ipilimumab and nivolumab (anti-PD-1). An increase in CA-US HIV RNA following infusion was noted, whereas anti-PD-1 alone had no effect on HIV-latency or the latent HIV-reservoir (141).…”

Interaction between hepatitis B virus infection and the efficacy of camrelizumab in combination with apatinib therapy in patients with hepatocellular carcinoma: a multicenter retrospective cohort study

“…It may be that viral antigens interfere with the anti-tumor effects of anti-PD-1 in the tumor immune microenvironment (TME). However, a sub-study of the Acquired Immunodeficiency Syndrome Malignancy Consortium-095 Study recently reported that anti-PD-1 alone had no effect on HIV-latency or the latent HIV-reservoir (20). More importantly, Sun et al (13) found no significant association between HBV loads and survival in HCC patients.…”