Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial

Orkin, Chloe; Molina, Jean‐Michel; Negredo, Eugènia; Arribas, José Ramón; Eron, Joseph J.; Landuyt, Erika Van; Lathouwers, Erkki; Hufkens, Veerle; Petrovic, Romana; Vanveggel, Simon; Opsomer, Magda; Ajana, F.; Bailey, Joseph; Benson, Paul M.; Berenguer, Juan; Bhatti, Laveeza; Blaxhult, Anders; Brar, Indira; Bredeek, U. Fritz; Brinson, Cynthia; Brunetta, Jason; Casado, José L.; Clarke, Amanda; Conway, Brian; Cotte, Laurent; Crofoot, GE; Cunningham, David; Vente, Jerome De; Wit, Stéphane De; DeJesus, Edwin; Dietz, CA; Dretler, Robin; Fehr, Jan; Felizarta, Franco; Fichtenbaum, Carl J.; Flamholc, Leo; Florence, Éric; Galindo, MJ; Gallant, Joel E.; Gąsiorowski, Jacek; Gatell, JM; Gathe, Joseph; Bg, Gazzard; Pm, Girard; Gisslén, Magnus; Gutiérrez, Félix; Gutierrez, Mdm; Hagins, DP; Halota, Waldemar; Henn, S; Wk, Henry; Horban, Andrzéj; Huhn, Gregory; Iribarren, J. A.; Jain, Mamta K.; Ma, Jun; Katlama, Christine; Klein, Marina B.; Knobel, Hernando; Lucasti, Christopher; Martorell, Claudia; McDonald, C; Mills, Anthony; Jm, Molina; Morales-Ramirez, Javier O; Mounzer, Karam; Moutschen, Michel; Murphy, Daniel; Nahass, Ronald; Olivet, H; Osiyemi, Olayemi; Pérez‐Valero, Ignacio; Piekarska, Anna; Pineda, Juan A.; Podzamczer, Daniel; Poizot‐Martin, Isabelle; Portilla, Joaquín; Post, Frank A.; Prelutsky, D; Pulido, Federico; Rachlis, Anita; Raffi, François; Ramgopal, Moti; Rashbaum, Bruce; Rauch, Angelika; Rey, David; Reynes, Jacques; Ricart, C; Richmond, Gary; Rivero, A.; Ruane, Peter; Gil, Inês; Scarsella, AJ; Scribner, Anita; Shafran, Stephen D.; Shalit, Peter; Shamblaw, David; Slim, Jihad; Stoeckle, Marcel; Tashima, K.; Teicher, Elina; Thalme, Anders; Ustianowski, Andrew; Wijngaerden, Eric Van; Vandekerckhove, Linos; Vandercam, Bernard; Voskuhl, Gene W.; Walmsley, Sharon; Ward, Doug; Waters, Laura; Wilkin, Aimee M.; Witor, Anita; Yazdanpanah, Yazdan

doi:10.1016/s2352-3018(17)30179-0

Cited by 88 publications

(122 citation statements)

References 20 publications

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“…No grade 3/4 or serious AEs, deaths, or discontinuations due to AEs occurred. The tolerability profile is consistent with earlier studies, with the most commonly reported AEs during the studies, headache and nausea, reported previously for studies of DRV, COBI, FTC, and TAF and in the ongoing phase 3 studies …”

Section: Discussionsupporting

confidence: 89%

“…Consistent with other DRV formulations, it is recommended that D/C/F/TAF be taken with food. Also in the ongoing phase 3 studies, the recommended intake for the D/C/F/TAF single‐tablet regimen and other DRV‐containing regimens is with food …”

Section: Discussionmentioning

confidence: 99%

“…The efficacy and safety of D/C/F/TAF in HIV‐1–infected patients is under investigation in 2 large, international, randomized phase 3 studies: AMBER in treatment‐naive, HIV‐1–infected adults (NCT02431247) and EMERALD in adults with virologically suppressed HIV‐1 (NCT02269917) . D/C/F/TAF showed noninferior virologic efficacy compared to DRV/COBI plus FTC/TDF in AMBER or switching from a boosted PI plus FTC/TDF in EMERALD through week 48, with significantly improved bone and renal biomarker safety and no development of DRV, primary PI or TDF/TAF resistance‐associated mutations …”

mentioning

confidence: 99%

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Bioequivalence of the Once‐Daily Single‐Tablet Regimen of Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Compared to Combined Intake of the Separate Agents and the Effect of Food on Bioavailability

Crauwels

Baugh

Landuyt

et al. 2018

Clinical Pharm in Drug Dev

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The effect of food on the bioavailability of the components of the once‐daily, single‐tablet human immunodeficiency virus (HIV) type 1 regimen containing darunavir (DRV 800 mg), cobicistat (COBI 150 mg), emtricitabine (FTC 200 mg), and tenofovir alafenamide (TAF 10 mg) (D/C/F/TAF) (NCT02475135) and the bioequivalence of D/C/F/TAF versus combined intake of the separate agents (NCT02578550) were evaluated. These were 2 phase 1, open‐label, randomized, 2‐period crossover studies (7‐day washout between treatments) in HIV‐negative healthy volunteers. Twenty‐four participants each received a single dose of D/C/F/TAF in fasted conditions (test) or after a standardized high‐fat breakfast (reference). Ninety‐six participants each received a single dose of D/C/F/TAF (test) or combined intake of a single DRV 800‐mg tablet, a COBI 150‐mg tablet, and an FTC/TAF 200/10‐mg tablet (reference), both after a standardized regular‐calorie, regular‐fat breakfast. Pharmacokinetic profiles for all D/C/F/TAF components, safety, and tolerability were assessed. Following D/C/F/TAF in fasted conditions, DRV peak concentration, area under the concentration‐time curve from time of administration until the last time point with a measurable concentration (AUC)last, and extrapolated to infinity (AUCinf) were lower by 45%, 34%, and 30%, respectively, compared with fed conditions, with no clinically relevant differences in COBI, FTC, or TAF exposures between fed and fasted conditions. In the bioequivalence study 90% confidence intervals of the geometric mean ratios of all main pharmacokinetic parameters were within the 80.00% to 125.00% bioequivalence limits for DRV, COBI, FTC, and TAF. No grade 3/4 adverse events (AEs), serious AEs, deaths, or discontinuations due to AEs occurred. D/C/F/TAF is bioequivalent to combined administration of the separate agents. Consistent with other (co)formulations of DRV, DRV exposure was lower in fasted than in fed conditions as evaluated when taken with food, so D/C/F/TAF should be taken with food.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Bioequivalence of the Once‐Daily Single‐Tablet Regimen of Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Compared to Combined Intake of the Separate Agents and the Effect of Food on Bioavailability

Crauwels

Baugh

Landuyt

et al. 2018

Clinical Pharm in Drug Dev

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“…60 Darunavir/cobicistat/emtricitabine/TAF maintained virologic suppression in patients switching from a boosted PI plus emtricitabine/TDF, even if there was previous virologic failure, provided there was no history of darunavir failure or darunavir-resistance mutations. 51 Elvitegravir/cobicistat/emtricitabine/TAF combined with darunavir taken once daily effectively maintained virologic suppression in patients with 2-class drug resistance (up to 3 thymidine analogue–associated mutations but no multi-NRTI or darunavir mutations)while taking multidrug regimens. 61 …”

Section: When and How To Switchmentioning

confidence: 99%

Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults

Saag

Benson

Gandhi

et al. 2018

JAMA

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IMPORTANCE Antiretroviral therapy (ART) is the cornerstone of prevention and management of HIV infection. OBJECTIVE To evaluate new data and treatments and incorporate this information into updated recommendations for initiating therapy, monitoring individuals starting therapy, changing regimens, and preventing HIV infection for individuals at risk. EVIDENCE REVIEW New evidence collected since the International Antiviral Society–USA 2016 recommendations via monthly PubMed and EMBASE literature searches up to April 2018; data presented at peer-reviewed scientific conferences. A volunteer panel of experts in HIV research and patient care considered these data and updated previous recommendations. FINDINGS ART is recommended for virtually all HIV-infected individuals, as soon as possible after HIV diagnosis. Immediate initiation (eg, rapid start), if clinically appropriate, requires adequate staffing, specialized services, and careful selection of medical therapy. An integrase strand transfer inhibitor (InSTI) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is generally recommended for initial therapy, with unique patient circumstances (eg, concomitant diseases and conditions, potential for pregnancy, cost) guiding the treatment choice. CD4 cell count, HIV RNA level, genotype, and other laboratory tests for general health and co-infections are recommended at specified points before and during ART. If a regimen switch is indicated, treatment history, tolerability, adherence, and drug resistance history should first be assessed; 2 or 3 active drugs are recommended for a new regimen. HIV testing is recommended at least once for anyone who has ever been sexually active and more often for individuals at ongoing risk for infection. Preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and appropriate monitoring is recommended for individuals at risk for HIV. CONCLUSIONS AND RELEVANCE Advances in HIV prevention and treatment with antiretroviral drugs continue to improve clinical management and outcomes for individuals at risk for and living with HIV.

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“…Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF; 800/150/200/10 mg) is an oral once‐daily single‐tablet regimen that is approved in Europe, Canada, and the United States. Studies of the protease inhibitor darunavir have demonstrated a durable virologic response, long‐term safety, and a high barrier to the development of resistance .…”

mentioning

confidence: 99%

Impact of Splitting or Crushing on the Relative Bioavailability of the Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Single‐Tablet Regimen

Brown

Thomas

McKenney

et al. 2018

Clinical Pharm in Drug Dev

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Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) is an oral once‐daily single‐tablet regimen for the treatment of human immunodeficiency virus‐1 infection. Different administration modalities for the D/C/F/TAF fixed‐dose combination tablet were explored in this phase 1 randomized, open‐label, 3‐period, 3‐treatment crossover study enrolling 30 healthy adults. The primary objective was to assess the relative bioavailability of each component after a single dose of D/C/F/TAF (800/150/200/10 mg) administered as a split or crushed tablet (tests) versus swallowed whole (reference). Pharmacokinetic parameters (noncompartmental analysis; logarithm‐transformed) for each component were compared using linear mixed‐effects modeling. For the split versus whole tablet, the bioavailabilities (maximum plasma concentration [Cmax] and area under the plasma concentration‐time curve [AUClast]) of each D/C/F/TAF component were comparable. For the crushed versus whole tablet, the bioavailabilities of darunavir, cobicistat, and emtricitabine were comparable, except for a 17% decrease in emtricitabine Cmax; the relative bioavailability of tenofovir alafenamide decreased by 29% and 19% for Cmax and AUClast, respectively. All intakes were safe and generally well tolerated. In summary, there was no clinically relevant impact on the bioavailability of D/C/F/TAF components when administered as a split tablet compared with a tablet swallowed whole. Administration of a crushed tablet resulted in a modest decrease in tenofovir alafenamide bioavailability; the clinical relevance of this change has not been assessed but is expected to be minimal based on the wide therapeutic window for this agent.

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Cited by 88 publications

References 20 publications

Bioequivalence of the Once‐Daily Single‐Tablet Regimen of Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Compared to Combined Intake of the Separate Agents and the Effect of Food on Bioavailability

Bioequivalence of the Once‐Daily Single‐Tablet Regimen of Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Compared to Combined Intake of the Separate Agents and the Effect of Food on Bioavailability

Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults

Impact of Splitting or Crushing on the Relative Bioavailability of the Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Single‐Tablet Regimen

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