TY - JOUR
T1 - 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
T2 - The AIDS Malignancy Consortium 095 Study
AU - Rasmussen, Thomas A.
AU - Rajdev, Lakshmi
AU - Rhodes, Ajantha
AU - Dantanarayana, Ashanti
AU - Tennakoon, Surekha
AU - Chea, Socheata
AU - Spelman, Tim
AU - Lensing, Shelly
AU - Rutishauser, Rachel
AU - Bakkour, Sonia
AU - Busch, Michael
AU - Siliciano, Janet D.
AU - Siliciano, Robert F.
AU - Einstein, Mark H.
AU - Dittmer, Dirk P.
AU - Chiao, Elizabeth
AU - Deeks, Steven G.
AU - Durand, Christine
AU - Lewin, Sharon R.
N1 - Funding Information:
The study was funded by the American Foundation for AIDS Research (amfAR; grant number 109226-58-RGRL to S. R. L.); the Australian National Health and Medical Research Council (NHMRC; grant number GNT1149990 to S. R. L.); the Australian Centre for HIV and Hepatitis Research (ACH2; Rasmussen 2019 to T. A. R.); and the National Institutes of Health funded Delaney AIDS Research Enterprise to find a cure (UM1AI126611) to S. R. L. The clinical trial was supported by a grant from the NCI to the AIDS Malignancy Consortium (grant number UM1 CA121947). D. P. D. was supported by public health service grants CA239583 and DE018304. C.D. was supported by the National Cancer Institute (grant number 5K23CA177321-05).
Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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.
AB - 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.
KW - HIV
KW - HIV latency
KW - anti–CTLA-4
KW - anti–PD-1
UR - http://www.scopus.com/inward/record.url?scp=85107569988&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85107569988&partnerID=8YFLogxK
U2 - 10.1093/cid/ciaa1530
DO - 10.1093/cid/ciaa1530
M3 - Article
C2 - 33677480
AN - SCOPUS:85107569988
SN - 1058-4838
VL - 73
SP - E1973-E1981
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
IS - 7
ER -