Dario Cattaneo1, Davide Minisci2, Sara Baldelli1, Cristina Mazzali3,4, Andrea Giacomelli2, Laura Milazzo2, Paola Meraviglia2, Chiara Resnati2, Giuliano Rizzardini2,5, Emilio Clementi6,7, Massimo Galli1, Cristina Gervasoni2. 1. Unit of Clinical Pharmacology, L. Sacco University Hospital, Milan, Italy. 2. Department of Infectious Disease, L. Sacco University Hospital, Milan, Italy. 3. Department of Management, Economics and Industrial Engineering (DIG), Politecnico di Milano, Milan, Italy. 4. Unit of Statistics and Biometrics, Department of Biomedical and Clinical Sciences, Hospital Luigi Sacco, Università degli Studi di Milano, Milan, Italy. 5. Department of Health Science, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa. 6. Department of Biomedical and Clinical Sciences, Clinical Pharmacology Unit, Consiglio Nazionale delle Ricerche Institute of Neuroscience, L. Sacco University Hospital, Università degli Studi di Milano, Milan, Italy. 7. E. Medea Scientific Institute, Bosisio Parini, Italy.
Abstract
BACKGROUND: The dose of tenofovir alafenamide is reduced from 25 to 10 mg daily when given with boosting agents. However, such dose reduction has never been adopted for tenofovir disoproxil fumarate (TDF). In this study, we aim to quantify the effect of cobicistat (COBI) both on tenofovir concentrations and TDF durability in real life setting. METHODS: HIV-positive patients receiving TDF-containing antiretroviral therapies with at least 1 assessment of tenofovir plasma trough concentrations were included in the study. Univariate and multivariate regression analyses were performed considering tenofovir concentration as the dependent variable and clinical characteristics as independent covariates. Subsequently, survival and Cox analyses were performed considering as the primary outcome TDF discontinuation for any reasons. RESULTS: Patients were given TDF with protease inhibitors/ritonavir (n = 212), non-nucleoside reverse transcriptase inhibitors (n = 176), integrase inhibitors (dolutegravir or raltegravir, n = 46), or with elvitegravir/COBI (ELV/COBI) (n = 76). By multivariate analysis, concomitant antiretroviral therapies resulted significantly associated with tenofovir levels, with the highest drug concentrations measured in patients given ELV/COBI. By survival analysis, we found that patients given TDF with ELV/COBI had the lowest rate of drug durability. Overall, these patients had a 2.3-fold increased risk to experience TDF discontinuation. CONCLUSIONS: Coadministration with COBI resulted in significantly higher tenofovir concentrations and higher TDF discontinuation compared with other antiretroviral regimens. Accordingly, the possibility that the lack of proper dose adjustment for TDF when given with COBI might have biased the safety comparisons with tenofovir alafenamide during registrative trials cannot be ruled out.
BACKGROUND: The dose of tenofovir alafenamide is reduced from 25 to 10 mg daily when given with boosting agents. However, such dose reduction has never been adopted for tenofovir disoproxil fumarate (TDF). In this study, we aim to quantify the effect of cobicistat (COBI) both on tenofovir concentrations and TDF durability in real life setting. METHODS: HIV-positive patients receiving TDF-containing antiretroviral therapies with at least 1 assessment of tenofovir plasma trough concentrations were included in the study. Univariate and multivariate regression analyses were performed considering tenofovir concentration as the dependent variable and clinical characteristics as independent covariates. Subsequently, survival and Cox analyses were performed considering as the primary outcome TDF discontinuation for any reasons. RESULTS:Patients were given TDF with protease inhibitors/ritonavir (n = 212), non-nucleoside reverse transcriptase inhibitors (n = 176), integrase inhibitors (dolutegravir or raltegravir, n = 46), or with elvitegravir/COBI (ELV/COBI) (n = 76). By multivariate analysis, concomitant antiretroviral therapies resulted significantly associated with tenofovir levels, with the highest drug concentrations measured in patients given ELV/COBI. By survival analysis, we found that patients given TDF with ELV/COBI had the lowest rate of drug durability. Overall, these patients had a 2.3-fold increased risk to experience TDF discontinuation. CONCLUSIONS: Coadministration with COBI resulted in significantly higher tenofovir concentrations and higher TDF discontinuation compared with other antiretroviral regimens. Accordingly, the possibility that the lack of proper dose adjustment for TDF when given with COBI might have biased the safety comparisons with tenofovir alafenamide during registrative trials cannot be ruled out.
Authors: Mary Morrow; Samantha MaWhinney; Ryan P Coyle; Stacey S Coleman; Edward M Gardner; Jia-Hua Zheng; Lucas Ellison; Lane R Bushman; Jennifer J Kiser; Peter L Anderson; Jose R Castillo-Mancilla Journal: J Infect Dis Date: 2019-07-19 Impact factor: 5.226
Authors: Jose R Castillo-Mancilla; Mary Morrow; Ryan P Coyle; Stacey S Coleman; Edward M Gardner; Jia-Hua Zheng; Lucas Ellison; Lane R Bushman; Jennifer J Kiser; Samantha Mawhinney; Peter L Anderson Journal: Clin Infect Dis Date: 2019-04-08 Impact factor: 9.079
Authors: Ellen F Eaton; Ashutosh Tamhane; Thibaut Davy-Mendez; Richard D Moore; W Christopher Mathews; Michael S Saag; Michael J Mugavero; Christina M Wyatt; Orlando M Gutierrez Journal: J Acquir Immune Defic Syndr Date: 2019-05-01 Impact factor: 3.731
Authors: Ryan P Coyle; Mary Morrow; Stacey S Coleman; Edward M Gardner; Jia-Hua Zheng; Lucas Ellison; Lane R Bushman; Jennifer J Kiser; Samantha MaWhinney; Peter L Anderson; Jose R Castillo-Mancilla Journal: J Antimicrob Chemother Date: 2020-06-01 Impact factor: 5.790
Authors: Nicola Squillace; Giorgio Bozzi; Elisa Colella; Andrea Gori; Alessandra Bandera Journal: Drug Des Devel Ther Date: 2018-10-29 Impact factor: 4.162