Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

doi:10.1089/AID.2019.0111

Clinical Trial

. 2020 Jan;36(1):48-57.

doi: 10.1089/AID.2019.0111. Epub 2019 Oct 21.

Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

Collaborators, Affiliations

Collaborators

AMBER and EMERALD Study Groups:
S De Wit, E Florence, L Vandekerckhove, B Vandercam, J Brunetta, M Klein, D Murphy, A Rachlis, S Walmsley, F Ajana, L Cotte, P-M Girard, C Katlama, J-M Molina, I Poizot-Martin, F Raffi, D Rey, J Reynes, E Teicher, Y Yazdanpanah, K Arastéh, M Bickel, J Bogner, S Esser, G Faetkenheuer, H Jessen, W Kern, J Rockstroh, C Spinner, H-J Stellbrink, A Stoehr, A Antinori, F Castelli, A Chirianni, A De Luca, A Di Biagio, M Galli, A Lazzarin, F Maggiolo, R Maserati, C Mussini, A Garlicki, J Gasiorowski, W Halota, A Horban, M Parczewski, A Piekarska, E Belonosova, O Chernova, N Dushkina, V Kulagin, E Ryamova, A Shuldyakov, N Sizova, O Tsybakova, E Voronin, A Yakovlev, A Antela, J R Arribas, J Berenguer, J Casado, V Estrada, M J Galindo, M Garcia Del Toro, J M Gatell, M Gorgolas, F Gutierrez, Mdm Gutierrez, E Negredo, J A Pineda, D Podzamczer, J Portilla Sogorb, A Rivero, R Rubio, P Viciana, I De Los Santos, A Clarke, B G Gazzard, M A Johnson, C Orkin, I Reeves, L Waters, P Benson, L Bhatti, F Bredeek, G Crofoot, D Cunningham, E DeJesus, J Eron, F Felizarta, R Franco, J Gallant, D Hagins, K Henry, D Jayaweera, C Lucasti, C Martorell, C McDonald, J McGowan, A Mills, J Morales-Ramirez, D Prelutsky, M Ramgopal, B Rashbaum, P Ruane, J Slim, A Wilkin, J deVente, S De Wit, E Florence, M Moutschen, E Van Wijngaerden, L Vandekerckhove, B Vandercam, J Brunetta, B Conway, M Klein, D Murphy, A Rachlis, S Shafran, S Walmsley, F Ajana, L Cotte, P-M Girard, C Katlama, J-M Molina, I Poizot-Martin, F Raffi, D Rey, J Reynes, E Teicher, Y Yazdanpanah, J Gasiorowski, W Halota, A Horban, A Piekarska, A Witor, J R Arribas, I Perez-Valero, J Berenguer, J Casado, J M Gatell, F Gutierrez, M J Galindo, Mdm Gutierrez, J A Iribarren, H Knobel, E Negredo, J A Pineda, D Podzamczer, J Portilla Sogorb, F Pulido, C Ricart, A Rivero, I Santos Gil, A Blaxhult, L Flamholc, M Gisslèn, A Thalme, J Fehr, A Rauch, M Stoeckle, A Clarke, B G Gazzard, M A Johnson, C Orkin, F Post, A Ustianowski, L Waters, J Bailey, P Benson, L Bhatti, I Brar, U F Bredeek, C Brinson, G Crofoot, D Cunningham, E DeJesus, C Dietz, R Dretler, J Eron, F Felizarta, C Fichtenbaum, J Gallant, J Gathe, D Hagins, S Henn, K W Henry, G Huhn, M Jain, C Lucasti, C Martorell, C McDonald, A Mills, J Morales-Ramirez, K Mounzer, R Nahass, H Olivet, O Osiyemi, D Prelutsky, M Ramgopal, B Rashbaum, G Richmond, P Ruane, A Scarsella, A Scribner, P Shalit, D Shamblaw, J Slim, K Tashima, G Voskuhl, D Ward, A Wilkin, J de Vente

Affiliations

¹ Janssen Pharmaceutica NV, Beerse, Belgium.
² Janssen Scientific Affairs, LLC, Titusville, New Jersey.
³ Janssen Research & Development LLC, Raritan, New Jersey.
⁴ Janssen Research & Development, Pennington, New Jersey.

PMID: 31516033
PMCID: PMC6944133
DOI: 10.1089/AID.2019.0111

Clinical Trial

Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

Erkki Lathouwers et al. AIDS Res Hum Retroviruses. 2020 Jan.

. 2020 Jan;36(1):48-57.

doi: 10.1089/AID.2019.0111. Epub 2019 Oct 21.

Collaborators

AMBER and EMERALD Study Groups:
S De Wit, E Florence, L Vandekerckhove, B Vandercam, J Brunetta, M Klein, D Murphy, A Rachlis, S Walmsley, F Ajana, L Cotte, P-M Girard, C Katlama, J-M Molina, I Poizot-Martin, F Raffi, D Rey, J Reynes, E Teicher, Y Yazdanpanah, K Arastéh, M Bickel, J Bogner, S Esser, G Faetkenheuer, H Jessen, W Kern, J Rockstroh, C Spinner, H-J Stellbrink, A Stoehr, A Antinori, F Castelli, A Chirianni, A De Luca, A Di Biagio, M Galli, A Lazzarin, F Maggiolo, R Maserati, C Mussini, A Garlicki, J Gasiorowski, W Halota, A Horban, M Parczewski, A Piekarska, E Belonosova, O Chernova, N Dushkina, V Kulagin, E Ryamova, A Shuldyakov, N Sizova, O Tsybakova, E Voronin, A Yakovlev, A Antela, J R Arribas, J Berenguer, J Casado, V Estrada, M J Galindo, M Garcia Del Toro, J M Gatell, M Gorgolas, F Gutierrez, Mdm Gutierrez, E Negredo, J A Pineda, D Podzamczer, J Portilla Sogorb, A Rivero, R Rubio, P Viciana, I De Los Santos, A Clarke, B G Gazzard, M A Johnson, C Orkin, I Reeves, L Waters, P Benson, L Bhatti, F Bredeek, G Crofoot, D Cunningham, E DeJesus, J Eron, F Felizarta, R Franco, J Gallant, D Hagins, K Henry, D Jayaweera, C Lucasti, C Martorell, C McDonald, J McGowan, A Mills, J Morales-Ramirez, D Prelutsky, M Ramgopal, B Rashbaum, P Ruane, J Slim, A Wilkin, J deVente, S De Wit, E Florence, M Moutschen, E Van Wijngaerden, L Vandekerckhove, B Vandercam, J Brunetta, B Conway, M Klein, D Murphy, A Rachlis, S Shafran, S Walmsley, F Ajana, L Cotte, P-M Girard, C Katlama, J-M Molina, I Poizot-Martin, F Raffi, D Rey, J Reynes, E Teicher, Y Yazdanpanah, J Gasiorowski, W Halota, A Horban, A Piekarska, A Witor, J R Arribas, I Perez-Valero, J Berenguer, J Casado, J M Gatell, F Gutierrez, M J Galindo, Mdm Gutierrez, J A Iribarren, H Knobel, E Negredo, J A Pineda, D Podzamczer, J Portilla Sogorb, F Pulido, C Ricart, A Rivero, I Santos Gil, A Blaxhult, L Flamholc, M Gisslèn, A Thalme, J Fehr, A Rauch, M Stoeckle, A Clarke, B G Gazzard, M A Johnson, C Orkin, F Post, A Ustianowski, L Waters, J Bailey, P Benson, L Bhatti, I Brar, U F Bredeek, C Brinson, G Crofoot, D Cunningham, E DeJesus, C Dietz, R Dretler, J Eron, F Felizarta, C Fichtenbaum, J Gallant, J Gathe, D Hagins, S Henn, K W Henry, G Huhn, M Jain, C Lucasti, C Martorell, C McDonald, A Mills, J Morales-Ramirez, K Mounzer, R Nahass, H Olivet, O Osiyemi, D Prelutsky, M Ramgopal, B Rashbaum, G Richmond, P Ruane, A Scarsella, A Scribner, P Shalit, D Shamblaw, J Slim, K Tashima, G Voskuhl, D Ward, A Wilkin, J de Vente

Affiliations

¹ Janssen Pharmaceutica NV, Beerse, Belgium.
² Janssen Scientific Affairs, LLC, Titusville, New Jersey.
³ Janssen Research & Development LLC, Raritan, New Jersey.
⁴ Janssen Research & Development, Pennington, New Jersey.

PMID: 31516033
PMCID: PMC6944133
DOI: 10.1089/AID.2019.0111

Abstract

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) ≥400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL <50 copies/mL) in EMERALD. Through week 48 across both studies, no darunavir, primary PI, or tenofovir resistance-associated mutations (RAMs) were observed in HIV-1 viruses of 1,125 participants receiving D/C/F/TAF or 629 receiving boosted darunavir plus emtricitabine/tenofovir-disoproxil-fumarate. In AMBER, the nucleos(t)ide analog reverse transcriptase inhibitor (N(t)RTI) RAM M184I/V was identified in HIV-1 of one participant during D/C/F/TAF treatment. M184V was detected pretreatment as a minority variant (9%). In EMERALD, in participants with prior VF and genoarchive data (N = 140; 98 D/C/F/TAF and 42 control), 4% had viruses with darunavir RAMs, 38% with emtricitabine RAMs, mainly at position 184 (41% not fully susceptible to emtricitabine), 4% with tenofovir RAMs, and 21% ≥ 3 thymidine analog-associated mutations (24% not fully susceptible to tenofovir) detected at screening. All achieved VL <50 copies/mL at week 48 or prior discontinuation. D/C/F/TAF has a high genetic barrier to resistance; no darunavir, primary PI, or tenofovir RAMs were observed through 48 weeks in AMBER and EMERALD. Only one postbaseline M184I/V RAM was observed in HIV-1 of an AMBER participant. In EMERALD, baseline archived RAMs to darunavir, emtricitabine, and tenofovir in participants with prior VF did not preclude virologic response.

Keywords: archived RAMs; darunavir/cobicistat/emtricitabine/TAF; deep sequencing; efficacy; resistance; single-tablet regimen.

PubMed Disclaimer

Conflict of interest statement

Janssen sponsored the studies. E.L., E.Y.W., K.B., B.B., A.G., J.J., E.M., E.V.L., M.O., and S.D.M. are all full-time employees of Janssen and potential stockholders of Johnson & Johnson. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.

E.L., E.Y.W., K.B., B.B., A.G., J.J., E.M., E.V.L., M.O., and S.D.M. were involved in the data analyses. All authors were involved in the development of the primary article, interpretation of data, and have read and approved the final version, and have met the criteria for authorship as established by the ICMJE.

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References

1. Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services; (Updated July 10, 2019). Available at www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf, accessed October7, 2019
1. EACS. European AIDS Clinical Society Guidelines, Version 9.1: (October 2018). Available at www.eacsociety.org/files/2018_guidelines-9.1-english.pdf, accessed October7, 2019
1. Saag MS, Benson CA, Gandhi RT, et al. : Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society-USA Panel. JAMA 2018;320:379–396 - PMC - PubMed
1. Orkin C, DeJesus E, Khanlou H, et al. : Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial. HIV Med 2013;14:49–59 - PubMed
1. Cahn P, Fourie J, Grinsztejn B, et al. : Week 48 analysis of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients. AIDS 2011;25:929–939 - PubMed

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[1] Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services; (Updated July 10, 2019). Available at www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf, accessed October7, 2019

[2] Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services; (Updated July 10, 2019). Available at www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf, accessed October7, 2019

[3] EACS. European AIDS Clinical Society Guidelines, Version 9.1: (October 2018). Available at www.eacsociety.org/files/2018_guidelines-9.1-english.pdf, accessed October7, 2019

[4] EACS. European AIDS Clinical Society Guidelines, Version 9.1: (October 2018). Available at www.eacsociety.org/files/2018_guidelines-9.1-english.pdf, accessed October7, 2019

[5] Saag MS, Benson CA, Gandhi RT, et al. : Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society-USA Panel. JAMA 2018;320:379–396 - PMC - PubMed

[6] Saag MS, Benson CA, Gandhi RT, et al. : Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society-USA Panel. JAMA 2018;320:379–396 - PMC - PubMed

[7] Orkin C, DeJesus E, Khanlou H, et al. : Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial. HIV Med 2013;14:49–59 - PubMed

[8] Orkin C, DeJesus E, Khanlou H, et al. : Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial. HIV Med 2013;14:49–59 - PubMed

[9] Cahn P, Fourie J, Grinsztejn B, et al. : Week 48 analysis of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients. AIDS 2011;25:929–939 - PubMed

[10] Cahn P, Fourie J, Grinsztejn B, et al. : Week 48 analysis of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients. AIDS 2011;25:929–939 - PubMed

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Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

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Affiliations

Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

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