Everolimus, an mTORC1/2 inhibitor, in ART-suppressed individuals who received solid organ transplantation : A prospective study
© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons..
Pharmacologic inhibition of the mammalian target of rapamycin (mTOR) in the setting of renal transplantation has previously been associated with lower human immunodeficiency virus 1 (HIV-1) DNA burden, and in vitro studies suggest that mTOR inhibition may lead to HIV transcriptional silencing. Because prospective clinical trials are lacking, we conducted an open-label, single-arm study to determine the impact of the broad mTOR inhibitor, everolimus, on residual HIV burden, transcriptional gene expression profiles, and immune responses in HIV-infected adult solid organ transplant (SOT) recipients on antiretroviral therapy. Whereas everolimus therapy did not have an overall effect on cell-associated HIV-1 DNA and RNA levels in the entire cohort, participants who maintained everolimus time-averaged trough levels >5 ng/mL during the first 2 months of therapy had significantly lower RNA levels up to 6 months after the cessation of study drug. Time-averaged everolimus trough levels significantly correlated with greater inhibition of mTOR gene pathway transcriptional activity. Everolimus treatment also led to decreased PD-1 expression on certain T cell subsets. These data support the rationale for further study of the effects of mTOR inhibition on HIV transcriptional silencing in non-SOT populations, either alone or in combination with other strategies. Trial Registration: ClinicalTrials.gov NCT02429869.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:21 |
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| Enthalten in: |
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons - 21(2021), 5 vom: 07. Mai, Seite 1765-1779 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Henrich, Timothy J [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 18.06.2021 Date Revised 24.01.2023 published: Print-Electronic ClinicalTrials.gov: NCT02429869 Citation Status MEDLINE |
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| doi: |
10.1111/ajt.16244 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM313553556 |
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| 100 | 1 | |a Henrich, Timothy J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Everolimus, an mTORC1/2 inhibitor, in ART-suppressed individuals who received solid organ transplantation |b A prospective study |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 18.06.2021 | ||
| 500 | |a Date Revised 24.01.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT02429869 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 The American Society of Transplantation and the American Society of Transplant Surgeons. | ||
| 520 | |a Pharmacologic inhibition of the mammalian target of rapamycin (mTOR) in the setting of renal transplantation has previously been associated with lower human immunodeficiency virus 1 (HIV-1) DNA burden, and in vitro studies suggest that mTOR inhibition may lead to HIV transcriptional silencing. Because prospective clinical trials are lacking, we conducted an open-label, single-arm study to determine the impact of the broad mTOR inhibitor, everolimus, on residual HIV burden, transcriptional gene expression profiles, and immune responses in HIV-infected adult solid organ transplant (SOT) recipients on antiretroviral therapy. Whereas everolimus therapy did not have an overall effect on cell-associated HIV-1 DNA and RNA levels in the entire cohort, participants who maintained everolimus time-averaged trough levels >5 ng/mL during the first 2 months of therapy had significantly lower RNA levels up to 6 months after the cessation of study drug. Time-averaged everolimus trough levels significantly correlated with greater inhibition of mTOR gene pathway transcriptional activity. Everolimus treatment also led to decreased PD-1 expression on certain T cell subsets. These data support the rationale for further study of the effects of mTOR inhibition on HIV transcriptional silencing in non-SOT populations, either alone or in combination with other strategies. Trial Registration: ClinicalTrials.gov NCT02429869 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a clinical research/practice | |
| 650 | 4 | |a immunosuppressant - mechanistic target of rapamycin: everolimus | |
| 650 | 4 | |a immunosuppression/immune modulation | |
| 650 | 4 | |a infection and infectious agents - viral: human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) | |
| 650 | 4 | |a infectious disease | |
| 650 | 4 | |a organ transplantation in general | |
| 650 | 4 | |a translational research/science | |
| 650 | 7 | |a Immunosuppressive Agents |2 NLM | |
| 650 | 7 | |a Pharmaceutical Preparations |2 NLM | |
| 650 | 7 | |a Everolimus |2 NLM | |
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| 650 | 7 | |a Mechanistic Target of Rapamycin Complex 1 |2 NLM | |
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| 700 | 1 | |a Schreiner, Corinna |e verfasserin |4 aut | |
| 700 | 1 | |a Cameron, Cheryl |e verfasserin |4 aut | |
| 700 | 1 | |a Hogan, Louise E |e verfasserin |4 aut | |
| 700 | 1 | |a Richardson, Brian |e verfasserin |4 aut | |
| 700 | 1 | |a Rutishauser, Rachel L |e verfasserin |4 aut | |
| 700 | 1 | |a Deitchman, Amelia N |e verfasserin |4 aut | |
| 700 | 1 | |a Chu, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Rogers, Rodney |e verfasserin |4 aut | |
| 700 | 1 | |a Thanh, Cassandra |e verfasserin |4 aut | |
| 700 | 1 | |a Gibson, Erica A |e verfasserin |4 aut | |
| 700 | 1 | |a Zarinsefat, Arya |e verfasserin |4 aut | |
| 700 | 1 | |a Bakkour, Sonia |e verfasserin |4 aut | |
| 700 | 1 | |a Aweeka, Francesca |e verfasserin |4 aut | |
| 700 | 1 | |a Busch, Michael P |e verfasserin |4 aut | |
| 700 | 1 | |a Liegler, Teri |e verfasserin |4 aut | |
| 700 | 1 | |a Baker, Christopher |e verfasserin |4 aut | |
| 700 | 1 | |a Milush, Jeffrey |e verfasserin |4 aut | |
| 700 | 1 | |a Deeks, Steven G |e verfasserin |4 aut | |
| 700 | 1 | |a Stock, Peter G |e verfasserin |4 aut | |
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