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; Eric Y Wong; Kimberley Brown; Bryan Baugh; Anne Ghys; John Jezorwski; El Ghazi Mohsine; Erika Van Landuyt; Magda Opsomer; Sandra De Meyer; AMBER and EMERALD Study Groups

doi:10.1089/AID.2019.0111

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

AIDS Res Hum Retroviruses. 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.

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.

Publication types

Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adenine / administration & dosage
Adenine / analogs & derivatives*
Adult
Alanine
Anti-HIV Agents / administration & dosage
Cobicistat / administration & dosage*
Darunavir / administration & dosage*
Drug Administration Schedule
Drug Combinations
Drug Resistance, Viral*
Emtricitabine / administration & dosage*
HIV Infections / drug therapy*
HIV Infections / epidemiology
HIV-1 / drug effects
Humans
Reverse Transcriptase Inhibitors / administration & dosage
Tablets / administration & dosage
Tenofovir / analogs & derivatives
Viral Load / drug effects

Substances

Anti-HIV Agents
Drug Combinations
Reverse Transcriptase Inhibitors
Tablets
Tenofovir
tenofovir alafenamide
Emtricitabine
Adenine
Cobicistat
Alanine
Darunavir

Associated data

ClinicalTrials.gov/NCT02431247
ClinicalTrials.gov/NCT02269917