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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 |
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| container_end_page | e1981 |
| container_issue | 7 |
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| container_title | Clinical infectious diseases |
| container_volume | 73 |
| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1093/cid/ciaa1530 |
| format | article |
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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.</description><identifier>ISSN: 1058-4838</identifier><identifier>EISSN: 1537-6591</identifier><identifier>DOI: 10.1093/cid/ciaa1530</identifier><identifier>PMID: 33677480</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>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</subject><ispartof>Clinical infectious diseases, 2021-10, Vol.73 (7), p.e1973-e1981</ispartof><rights>The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.</rights><rights>The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c384t-a6f239259c8a0ef09f8456456ee03ca38a3db184d4be925ea8e18e22d8c073c23</citedby><cites>FETCH-LOGICAL-c384t-a6f239259c8a0ef09f8456456ee03ca38a3db184d4be925ea8e18e22d8c073c23</cites><orcidid>0000-0001-5354-2442</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33677480$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rasmussen, Thomas A</creatorcontrib><creatorcontrib>Rajdev, Lakshmi</creatorcontrib><creatorcontrib>Rhodes, Ajantha</creatorcontrib><creatorcontrib>Dantanarayana, Ashanti</creatorcontrib><creatorcontrib>Tennakoon, Surekha</creatorcontrib><creatorcontrib>Chea, Socheata</creatorcontrib><creatorcontrib>Spelman, Tim</creatorcontrib><creatorcontrib>Lensing, Shelly</creatorcontrib><creatorcontrib>Rutishauser, Rachel</creatorcontrib><creatorcontrib>Bakkour, Sonia</creatorcontrib><creatorcontrib>Busch, Michael</creatorcontrib><creatorcontrib>Siliciano, Janet D</creatorcontrib><creatorcontrib>Siliciano, Robert F</creatorcontrib><creatorcontrib>Einstein, Mark H</creatorcontrib><creatorcontrib>Dittmer, Dirk P</creatorcontrib><creatorcontrib>Chiao, Elizabeth</creatorcontrib><creatorcontrib>Deeks, Steven G</creatorcontrib><creatorcontrib>Durand, Christine</creatorcontrib><creatorcontrib>Lewin, Sharon R</creatorcontrib><title>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</title><title>Clinical infectious diseases</title><addtitle>Clin Infect Dis</addtitle><description>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.
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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.</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>33677480</pmid><doi>10.1093/cid/ciaa1530</doi><orcidid>https://orcid.org/0000-0001-5354-2442</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Clinical infectious diseases, 2021-10, Vol.73 (7), p.e1973-e1981 |
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| source | Oxford University Press Journals |
| 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 |
| title | 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 |
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