Cargando…

Phase IIIb, open-label single-arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1-infected treatment-nave adults

INTRODUCTION: COBI, a PK enhancer with no ARV activity is a more selective cytochrome P450 (CYP)3A inhibitor than ritonavir (RTV), does not induce CYP isozymes, and thus has less potential for drug-drug interactions. COBI boosts DRV PK as effectively as RTV in healthy volunteers. MATERIALS AND METHO...

Descripción completa

Detalles Bibliográficos
Autores principales: Tashima, Karen, Crofoot, Gordon, Tomaka, Frank L, Kakuda, Thomas N, Brochot, Anne, Vanveggel, Simon, Opsomer, Magda, Garner, William, Margot, Nicolas, Custodio, Joseph M, Fordyce, Marshall W, Szwarcberg, Javier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International AIDS Society 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225446/
https://www.ncbi.nlm.nih.gov/pubmed/25397516
http://dx.doi.org/10.7448/IAS.17.4.19772
_version_ 1782343509398781952
author Tashima, Karen
Crofoot, Gordon
Tomaka, Frank L
Kakuda, Thomas N
Brochot, Anne
Vanveggel, Simon
Opsomer, Magda
Garner, William
Margot, Nicolas
Custodio, Joseph M
Fordyce, Marshall W
Szwarcberg, Javier
author_facet Tashima, Karen
Crofoot, Gordon
Tomaka, Frank L
Kakuda, Thomas N
Brochot, Anne
Vanveggel, Simon
Opsomer, Magda
Garner, William
Margot, Nicolas
Custodio, Joseph M
Fordyce, Marshall W
Szwarcberg, Javier
author_sort Tashima, Karen
collection PubMed
description INTRODUCTION: COBI, a PK enhancer with no ARV activity is a more selective cytochrome P450 (CYP)3A inhibitor than ritonavir (RTV), does not induce CYP isozymes, and thus has less potential for drug-drug interactions. COBI boosts DRV PK as effectively as RTV in healthy volunteers. MATERIALS AND METHODS: This 48-week, phase IIIb, open-label, single-arm, US multicentre study (NCT01440569) included HIV-infected treatment-nave and experienced adults with no DRV RAMs, viral load (VL) ≥1000 c/mL, eGFR ≥80 mL/min and genotypic sensitivity to investigator-selected N[t]RTIs. Patients received DRV/COBI 800/150 mg qd (as single agents) plus two fully active N[t]RTIs. The primary endpoint was any treatment-emergent grade 3 or 4 AEs through Week 24. We report 48-week safety, efficacy and PK/PD results in treatment-nave patients. RESULTS: Of 313 ITT patients, 295 were treatment-nave (94%). In the treatment-nave cohort, 90% were male, 60% white and 294 (99.7%) received a TDF-containing regimen. Median baseline (BL) VL was 4.8 log(10) c/mL and CD4(+) 370 cells/mm(3). Treatment-emergent grade 3 or 4 AEs regardless of causality were reported in 21 (7%) patients. AEs regardless of causality (any grade; ≥10% of patients) were: diarrhoea (27%), nausea (23%), URTI (15%) and headache (12%). Sixteen (5%) patients had AEs leading to study drug discontinuation, most frequently rash (three patients), hypersensitivity and nausea (two patients each). Consistent with the known inhibition of tubular creatinine secretion by COBI, there was a mean increase from BL in serum creatinine by week 2 (0.09 mg/dL), remaining stable through week 48 (mean 0.10 mg/dL increase from BL). At week 48, 83% of patients achieved VL<50 c/mL; FDA Snapshot); median increase in CD4(+) was 169 cells/mm(3). Eight patients met the criteria for resistance testing. M184V was detected in one pt receiving FTC. New primary RAMs were not detected in the other seven patients. The mean population PK-derived DRV AUC(24h) was 100,620 ng.h/mL and C(0h) 2,105 ng/mL (n=281). There were no clinically relevant relationships between DRV exposure and virologic response, AEs or laboratory parameters. CONCLUSIONS: The DRV PK of DRV/COBI was consistent with historical data for DRV/RTV. DRV/COBI 800/150 mg qd plus two N(t)RTIs had an 83% response and was well tolerated through Week 48. These results are similar to published data for DRV/RTV 800/100 mg qd, and support the use of DRV/COBI 800/150 mg qd in treatment-nave patients.
format Online
Article
Text
id pubmed-4225446
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher International AIDS Society
record_format MEDLINE/PubMed
spelling pubmed-42254462014-11-12 Phase IIIb, open-label single-arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1-infected treatment-nave adults Tashima, Karen Crofoot, Gordon Tomaka, Frank L Kakuda, Thomas N Brochot, Anne Vanveggel, Simon Opsomer, Magda Garner, William Margot, Nicolas Custodio, Joseph M Fordyce, Marshall W Szwarcberg, Javier J Int AIDS Soc Poster Sessions – Abstract P240 INTRODUCTION: COBI, a PK enhancer with no ARV activity is a more selective cytochrome P450 (CYP)3A inhibitor than ritonavir (RTV), does not induce CYP isozymes, and thus has less potential for drug-drug interactions. COBI boosts DRV PK as effectively as RTV in healthy volunteers. MATERIALS AND METHODS: This 48-week, phase IIIb, open-label, single-arm, US multicentre study (NCT01440569) included HIV-infected treatment-nave and experienced adults with no DRV RAMs, viral load (VL) ≥1000 c/mL, eGFR ≥80 mL/min and genotypic sensitivity to investigator-selected N[t]RTIs. Patients received DRV/COBI 800/150 mg qd (as single agents) plus two fully active N[t]RTIs. The primary endpoint was any treatment-emergent grade 3 or 4 AEs through Week 24. We report 48-week safety, efficacy and PK/PD results in treatment-nave patients. RESULTS: Of 313 ITT patients, 295 were treatment-nave (94%). In the treatment-nave cohort, 90% were male, 60% white and 294 (99.7%) received a TDF-containing regimen. Median baseline (BL) VL was 4.8 log(10) c/mL and CD4(+) 370 cells/mm(3). Treatment-emergent grade 3 or 4 AEs regardless of causality were reported in 21 (7%) patients. AEs regardless of causality (any grade; ≥10% of patients) were: diarrhoea (27%), nausea (23%), URTI (15%) and headache (12%). Sixteen (5%) patients had AEs leading to study drug discontinuation, most frequently rash (three patients), hypersensitivity and nausea (two patients each). Consistent with the known inhibition of tubular creatinine secretion by COBI, there was a mean increase from BL in serum creatinine by week 2 (0.09 mg/dL), remaining stable through week 48 (mean 0.10 mg/dL increase from BL). At week 48, 83% of patients achieved VL<50 c/mL; FDA Snapshot); median increase in CD4(+) was 169 cells/mm(3). Eight patients met the criteria for resistance testing. M184V was detected in one pt receiving FTC. New primary RAMs were not detected in the other seven patients. The mean population PK-derived DRV AUC(24h) was 100,620 ng.h/mL and C(0h) 2,105 ng/mL (n=281). There were no clinically relevant relationships between DRV exposure and virologic response, AEs or laboratory parameters. CONCLUSIONS: The DRV PK of DRV/COBI was consistent with historical data for DRV/RTV. DRV/COBI 800/150 mg qd plus two N(t)RTIs had an 83% response and was well tolerated through Week 48. These results are similar to published data for DRV/RTV 800/100 mg qd, and support the use of DRV/COBI 800/150 mg qd in treatment-nave patients. International AIDS Society 2014-11-02 /pmc/articles/PMC4225446/ /pubmed/25397516 http://dx.doi.org/10.7448/IAS.17.4.19772 Text en © 2014 Tashima K et al; licensee International AIDS Society http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Poster Sessions – Abstract P240
Tashima, Karen
Crofoot, Gordon
Tomaka, Frank L
Kakuda, Thomas N
Brochot, Anne
Vanveggel, Simon
Opsomer, Magda
Garner, William
Margot, Nicolas
Custodio, Joseph M
Fordyce, Marshall W
Szwarcberg, Javier
Phase IIIb, open-label single-arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1-infected treatment-nave adults
title Phase IIIb, open-label single-arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1-infected treatment-nave adults
title_full Phase IIIb, open-label single-arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1-infected treatment-nave adults
title_fullStr Phase IIIb, open-label single-arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1-infected treatment-nave adults
title_full_unstemmed Phase IIIb, open-label single-arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1-infected treatment-nave adults
title_short Phase IIIb, open-label single-arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1-infected treatment-nave adults
title_sort phase iiib, open-label single-arm trial of darunavir/cobicistat (drv/cobi): week 48 subgroup analysis of hiv-1-infected treatment-nave adults
topic Poster Sessions – Abstract P240
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225446/
https://www.ncbi.nlm.nih.gov/pubmed/25397516
http://dx.doi.org/10.7448/IAS.17.4.19772
work_keys_str_mv AT tashimakaren phaseiiibopenlabelsinglearmtrialofdarunavircobicistatdrvcobiweek48subgroupanalysisofhiv1infectedtreatmentnaveadults
AT crofootgordon phaseiiibopenlabelsinglearmtrialofdarunavircobicistatdrvcobiweek48subgroupanalysisofhiv1infectedtreatmentnaveadults
AT tomakafrankl phaseiiibopenlabelsinglearmtrialofdarunavircobicistatdrvcobiweek48subgroupanalysisofhiv1infectedtreatmentnaveadults
AT kakudathomasn phaseiiibopenlabelsinglearmtrialofdarunavircobicistatdrvcobiweek48subgroupanalysisofhiv1infectedtreatmentnaveadults
AT brochotanne phaseiiibopenlabelsinglearmtrialofdarunavircobicistatdrvcobiweek48subgroupanalysisofhiv1infectedtreatmentnaveadults
AT vanveggelsimon phaseiiibopenlabelsinglearmtrialofdarunavircobicistatdrvcobiweek48subgroupanalysisofhiv1infectedtreatmentnaveadults
AT opsomermagda phaseiiibopenlabelsinglearmtrialofdarunavircobicistatdrvcobiweek48subgroupanalysisofhiv1infectedtreatmentnaveadults
AT garnerwilliam phaseiiibopenlabelsinglearmtrialofdarunavircobicistatdrvcobiweek48subgroupanalysisofhiv1infectedtreatmentnaveadults
AT margotnicolas phaseiiibopenlabelsinglearmtrialofdarunavircobicistatdrvcobiweek48subgroupanalysisofhiv1infectedtreatmentnaveadults
AT custodiojosephm phaseiiibopenlabelsinglearmtrialofdarunavircobicistatdrvcobiweek48subgroupanalysisofhiv1infectedtreatmentnaveadults
AT fordycemarshallw phaseiiibopenlabelsinglearmtrialofdarunavircobicistatdrvcobiweek48subgroupanalysisofhiv1infectedtreatmentnaveadults
AT szwarcbergjavier phaseiiibopenlabelsinglearmtrialofdarunavircobicistatdrvcobiweek48subgroupanalysisofhiv1infectedtreatmentnaveadults