Single center, open label dose escalating trial evaluating once weekly oral ixazomib in ART-suppressed, HIV positive adults and effects on HIV reservoir size in vivo.

Autor:	Cummins NW; Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA., Baker J; Division of Infectious Diseases, Hennepin Healthcare, Minneapolis, Minnesota, USA., Chakraborty R; Division of Pediatric Infectious Diseases, Mayo Clinic, Rochester, MN., Dean PG; Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA., Garcia-Rivera E; nference, Cambridge, Massachusetts, USA., Krogman A; Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA., Kumar S; Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA., Kuzmichev YV; Department of Infectious Disease Research, Southern Research, Frederick, Maryland, USA., Laird GM; Accelevir Diagnostics, Baltimore, MD, USA., Landay A; Division of Geriatrics, Rush University Medical Center, Chicago, IL, USA., Lichterfeld M; Ragon Institute of MGH, MIT, and Harvard; Brigham and Women's Hospital, Boston, MA, USA., Mahmood M; Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA., Martinson J; Division of Geriatrics, Rush University Medical Center, Chicago, IL, USA., Maynes M; Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA., Natesampillai S; Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA., Rajkumar V; Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA., Rassadkina Y; Ragon Institute of MGH, MIT, and Harvard; Brigham and Women's Hospital, Boston, MA, USA., Ritter KD; Accelevir Diagnostics, Baltimore, MD, USA., Rivera CG; Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA., Rizza SA; Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA., Subramanian K; Department of Infectious Disease Research, Southern Research, Frederick, Maryland, USA., Tande AJ; Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA., Wonderlich ER; Department of Infectious Disease Research, Southern Research, Frederick, Maryland, USA., Whitaker JA; Division of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA., Zeuli J; Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA., Badley AD; Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.; Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Jazyk:	angličtina
Zdroj:	EClinicalMedicine [EClinicalMedicine] 2021 Nov 29; Vol. 42, pp. 101225. Date of Electronic Publication: 2021 Nov 29 (Print Publication: 2021).
DOI:	10.1016/j.eclinm.2021.101225
Abstrakt:	Background: Achieving a functional or sterilizing cure for HIV will require identification of therapeutic interventions that reduce HIV reservoir size in infected individuals. Proteasome inhibitors, such as ixazomib, impact multiple aspects of HIV biology including latency, transcription initiation, viral replication, and infected cell killing through the HIV protease - Casp8p41 pathway, resulting in latency reversal and reduced measures of HIV reservoir size ex vivo. Methods: We conducted a phase 1b/2a dose escalating, open label trial of weekly oral ixazomib for 24 weeks in antiretroviral (ART)-suppressed, HIV positive adults (NCT02946047). The study was conducted from March 2017 to August 2019 at two tertiary referral centers in the United States. The primary outcomes were safety and tolerability of oral ixazomib. Secondary outcomes included changes in immunologic markers and estimates of HIV reservoir size after ixazomib treatment. Findings: Sixteen participants completed the study. Ixazomib up to 4mg weekly was safe and well-tolerated, yielding no treatment-emergent events above grade 1. In exploratory analyses, ixazomib treatment was associated with detectable viremia that was below the lower limit of quantification (LLQ) in 9 participants, and viremia that was above LLQ in 4 of 16 participants. While treatment was associated with reduced CD4 counts [baseline 783 cells/ mm 3 vs. week-24 724 cells/ mm 3 p=0.003], there were no changes in markers of cellular activation, exhaustion or inflammation. Total HIV DNA and proviral sequencing were not altered by ixazomib treatment. Intact proviral DNA assay (IPDA) identified intact proviruses in 14 patients pre-treatment, and in 10/14 of those subjects post treatment values were reduced (P=0.068), allowing a calculated intact proviral half life of 0.6 years (95% CI 0.3, 2.5), compared to 7.1 years (95% CI 3.9, 18, p=0.004) in historical controls. Differentiation Quantitative Viral Outgrowth Assays (dQVOA) identified measurable proviruses in 15 subjects pre-treatment; post-treatment values were numerically reduced in 9, but overall differences were not significantly different. Interpretation: Our study successfully met its primary endpoint of demonstrating the safety of ixazomib for 24 weeks in HIV infected persons. Exploratory analyses suggest that the effects observed ex vivo of latency reversal and reductions in HIV reservoir size, also occur in vivo. Future controlled studies of ixazomib are warranted. Funding: This study was funded by Millennium Pharmaceuticals Inc..; the Mayo Clinic Foundation; the National Institutes of Health, including the National Institute of Allergy and Infectious Diseases, Division of AIDS, the National Heart, Lung and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the National Institute on Drug Abuse. Mayo Clinic also acknowledges generous funding support from Mr. Joseph T. and Mrs. Michele P. Betten. Competing Interests: NWC was supported by R56 AI145407-01A. ADB was supported by R01 AI110173, R01 AI120698; Amfar (#109593). ML is supported by NIH grants AI130005, AI117841, AI152979, DK120387, DA047034, AI120008. RC is supported by NIH grants 1U01AI131566-0, 1R01HD097843-01,1R21HD103498-01. This project was conducted in part by Southern Research using federal funds from the Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health under contract HHSN272201500017C entitled “Quantitative Viral Outgrowth Assay (QVOA) Service Resource. This work was also supported by UM1AI164562, co-funded by National Heart, Lung and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute on Drug Abuse and the National Institute of Allergy and Infectious Diseases. ADB is a paid consultant for Abbvie, Gilead, Freedom Tunnel, Pinetree therapeutics Primmune, Immunome, MarPam, and Flambeau Diagnostics, is a paid member of the DSMB for Corvus Pharmaceuticals, Equilium, and Excision Biotherapeutics, has received fees for speaking for Reach MD and Medscape, owns equity for scientific advisory work in Zentalis and Nference, and is founder and President of Splissen therapeutics. Mayo Clinic has filed a patent on the use of ixazomib in HIV positive persons. GML is an employee of and owns equity in Accelevir Diagnostics. NWC received funding from Takeda (Millennium Pharmaceuticals Inc) to conduct the trial, including professional time. AJT receives honoraria from Uptodate.com for writing unrelated to this topic. JZ serves on the advisory board for ViiV. SK receives research support for clinical trials from Abbvie, Celgene, Janssen, Takeda, Adapative, KITE, Medimmune/ Astra Zeneca, Merck, Novartis, Roche and Sanofi. SK is an advisory board member for Abbvie, Celgene, Janssen, Takeda, Adaptive, KITE, and Medimmune/ Astra Zeneca. SK participates in an independent review committee for Oncopeptides. (© 2021 The Author(s).)
Databáze:	MEDLINE
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