Antiviral Research 170 (2019) 104543 Contents lists available at ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral Week 96 efficacy and safety results of the phase 3, randomized EMERALD T trial to evaluate switching from boosted-protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the once daily, single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in treatment-experienced, virologically- suppressed adults living with HIV-1 Joseph J. Erona,∗, Chloe Orkinb, Douglas Cunninghamc, Federico Pulidod, Frank A. Poste, Stéphane De Witf, Erkki Lathouwersg, Veerle Hufkensg, John Jezorwskih, Romana Petrovicg, Kimberley Browng, Erika Van Landuytg, Magda Opsomerg, on behalf of the EMERALD study group (S. De Witi, E. Florencej, M. Moutschenk, E. Van Wijngaerdenl, L. Vandekerckhovem, B. Vandercamn, J. Brunettao, B. Conwayp, M. Kleinq, D. Murphyr, A. Rachliss, S. Shafrant,u, S. Walmsleyv, F. Ajanaw, L. Cottex, P.-M. Girardyy, C. Katlamaz, J.-M. Molinaaa, I. Poizot-Martinab, F. Raffiac, D. Reyad, J. Reynesae, E. Teicheraf, Y. Yazdanpanahag, J. Gasiorowskiah, W. Halotaai, A. Horbanaj, A. Piekarskaak, A. Witoral, J.R. Arribasam, I. Perez-Valeroan, J. Berenguerao, J. Casadoap, J.M. Gatellaq, F. Gutierrezar, M.J. Galindoas, M.D.M. Gutierrezat, J.A. Iribarrenau, H. Knobelav, E. Negredoaw, J.A. Pinedaax, D. Podzamczeray, J.Portilla Sogorbaz, F. Pulidoba, C. Ricartbb, A. Riverobc, I. Santos Gilbd, A. Blaxhultbe, L. Flamholcbf, M. Gisslènbg, A. Thalmebh, J. Fehrbi, A. Rauchbj, M. Stoecklebk, A. Clarkebl, B.G. Gazzardbm, M.A. Johnsonbn, C. Orkinbo, F. Postbp, A. Ustianowskibq, L. Watersbr, J. Baileybs, P. Bensonbt, L. Bhattibu, I. Brarbv, U.F. Bredeekbw, C. Brinsonbx, G. Crofootby, D. Cunninghambz, E. DeJesusca, C. Dietzcb, R. Dretlercc, J. Eroncd, F. Felizartace, C. Fichtenbaumcf, J. Gallantcg, J. Gathech, D. Haginsci, S. Henncj, W.K. Henryck, G. Huhncl, M. Jaincm, C. Lucasticn, C. Martorellco, C. McDonaldcp, A. Millscq, J. Morales-Ramirezcr, K. Mounzercs, R. Nahassct, H. Olivetcu, O. Osiyemicv, D. Prelutskycw, M. Ramgopalcx, B. Rashbaumcy, G. Richmondcz, P. Ruaneda, A. Scarselladb, A. Scribnerdc, P. Shalitdd, D. Shamblawde, J. Slimdf, K. Tashimadg, G. Voskuhldh, D. Warddi, A. Wilkindj, J. de Ventedk) a University of North Carolina School of Medicine, Chapel Hill, NC, USA b Queen Mary University, London, UK c Pueblo Family Physicians, Phoenix, AZ, USA d HIV Unit, Hospital 12 de Octubre, imas12, UCM, Madrid, Spain e King's College Hospital NHS Foundation Trust, London, United Kingdom f Saint-Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium g Janssen Pharmaceutica NV, Beerse, Belgium h Janssen Research & Development, Pennington, NJ, USA i Saint-Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium j Institute of Tropical Medicine, Antwerp, Belgium k Infectious Diseases department, Liège University Hospital, Liège, Belgium l Department of General Internal Medicine, University Hospitals, KU Leuven - University of Leuven, Belgium m Ghent University and Ghent University Hospital, Ghent, Belgium n AIDS Reference center, Cliniques Universitaires Saint-Luc, 1200, Brussels, Belgium ∗ Corresponding author. The University of North Carolina School of Medicine, Chapel Hill, NC, 27599-7215, USA. E-mail address: jeron@med.unc.edu (J.J. Eron). https://doi.org/10.1016/j.antiviral.2019.104543 Available online 04 July 2019 0166-3542/ © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). J.J. Eron, et al. Antiviral Research 170 (2019) 104543 o Maple Leaf Medical Clinic, Toronto, Canada p Vancouver Infectious Diseases Center, Vancouver, British Columbia, Canada q Division of Infectious Diseases, Faculty of Medicine, McGill University Health Centre, Montreal, QC, Canada r Institut national de santé publique du Québec, Montréal, QC, Canada s Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada t Department of Medicine, University of Toronto, Toronto, Ontario, Canada u Department of Medicine, University of Alberta, Edmonton, Canada v University Health Network, Toronto, ON, Canada w Infectious Diseases Department, Tourcoing Hospital, Tourcoing, France x Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Lyon, France y University Pierre & Marie Curie, Paris, France z HIV Clinical Research Unit, Hôpital pitié-Salpêtrière, Paris, France aa Department of Infectious Diseases, St-Louis Hospital APHP, University of Paris Diderot, Paris, France ab Clinical Immuno-Hematology Department, Aix-Marseille University, Sainte-Marguerite University Hospital and Inserm U912, Marseille, France ac CHU Hôtel Dieu, Nantes, France ad Le Trait d'Union, HIV-Infection Care Center, Hôpitaux Universitaires de Strasbourg, Strasbourg, France ae Montpellier University Hospital, Montpellier, France af Infectious Diseases Department, APHP, Hôpital Bicêtre, Le Kremlin Bicêtre, France ag 14AP-HP Bichat, Paris, France ah Independent Laboratory for Monitoring Infections among Drug Users at the Department of Infectious Diseases, Liver Disease and Acquired Immune Deficiencies, Wroclaw Medical University, Poland ai Department of Infectious Diseases and Hepatology, Nicolaus Copernicus University, Bydgoszcz, Poland aj Medical University of Warsaw, Department for Adult's Infectious Diseases, Warsaw, Poland ak Department of Infectious Diseases and Hepatology , Medical University of Lodz, Lodz, Poland al Regional Hospital, Out-Patient's Clinic for Immune Deficiency, Chorzów, Poland am Hospital Universitario La Paz, IdiPAZ, Madrid, Spain an Department of La Paz Hospital, Madrid, Spain ao Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain ap Department of Infectious Diseases, Ramon y Cajal Hospital, Madrid, Spain aq Infectious Diseases Department, HCB, Barcelona, Spain ar Infectious Diseases Unit, Hospital Universitario de Elche, Alicante, Spain as Hospital Clínico Universitario de Valencia, Valencia, Spain at Department of Infectious Diseases, HIV Infection Unit, Hospital de la Santa Creu i Sant Pau, Institut de Recerca del Hospital de la Santa Creu i Sant Pau, Barcelona, Spain au Hospital Universitario Donostia, San Sebastián, Spain av Hospital del Mar, Universitat Autonòma de Barcelona, Barcelona, Spain aw Lluita contra la Sida Foundation, Germans Trias i Pujol University Hospital, Barcelona, Spain ax Unit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Seville, Spain ay dIDIBELL-Hospital Universitari de Bellvitge, L’Hospitalet, Barcelona, Spain az HIV Unit, Hospital 12 de Octubre, imas12, UCM, Madrid, Spain ba Medicina Interna, Hospital General Universitario de Alicante, Alicante, Spain bb Department of Microbiology, School of Medicine, University of Valencia, Spain bc Infectious Diseases Unit, Hospital Universitario Reina Sofía, Instituto Maimonides de Investigación Biomedica de Córdoba IMIBIC Cordoba University, Cordoba, Spain bd Unidad de Enfermedades Infecciosas, Hospital Universitario de la Princesa, Madrid, Spain be Department of Infectious Diseases, Venhälsan, Södersjukhuset, Stockholm, Sweden bf Department of Infectious Diseases, Malmö University Hospital, 205 02 Malmö, Sweden bg Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden bh Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden bi Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland bj Department of Infectious Diseases, Bern University Hospital Inselspital, University of Bern, Bern, Switzerland bk Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital of Basel and University of Basel, Basel, Switzerland bl Claude Nicol Centre, Royal Sussex County Hospital, Brighton and Sussex University Hospitals NHS Trust, Brighton, UK bm St. Stephen's Centre, Department of HIV/Genito-Urinary Medicine, Chelsea and Westminster Hospital, London, UK bn Queen Mary University, London, UK bo Department of HIV Medicine, Royal Free London NHS Foundation Trust, London, UK bp King's College Hospital NHS Foundation Trust, London, UK bq Regional Infectious Diseases Unit, North Manchester General Hospital, Manchester, UK br University College London Hospital, London, UK bs Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA bt Be Well Medical, Berkley, MI, USA bu AIDS Healthcare Foundation, Beverly Hills, California, USA bv Henry Ford Hospital, Detroit, MI, USA bw Metropolis Medical PC, San Francisco, CA, USA bx Central Texas Clinical Research, Austin, TX, USA by The Crofoot Research Center, Houston, TX, USA bz University of North Carolina School of Medicine, Chapel Hill, NC, USA ca Pueblo Family Physicians, Phoenix, AZ, USA cb Orlando Immunology Center, Orlando, FL, USA cc HIV Medicine, Kansas City Free Health Clinic, Kansas City, MO, USA cd Infectious Disease Specialists of Atlanta, Atlanta, GA, USA ce Private Practice, 3535 San Dimas Street, Suite 24, Bakersfield, CA 93301, USA cf University of Cincinnati College of Medicine, Cincinnati, OH, USA cg Southwest CARE Center, Santa Fe, New Mexico, USA ch Therapeutic Concepts, Houston, TX, USA ci Georgia Department of Public Health, Coastal Health District, Chatham Care Center, Savannah, GA, USA cj Whitman-Walker Health, Washington, DC, USA ck Department of Medicine, University of Minnesota Washington University School of Medicine, St. Louis, Missouri, USA cl Ruth M. Rothstein CORE Center, Chicago, IL, USA cm Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA cn South Jersey Infectious Disease, Somers Point, NJ, USA 2 J.J. Eron, et al. Antiviral Research 170 (2019) 104543 co Infectious Disease and The Research Institute, Springfield, MA, USA cp Tarrant County Infectious Disease Associates, Fort Worth, TX, USA cq Southern California Men’s Medical Group, Los Angeles, California, USA cr Clinical Research Puerto Rico Inc., San Juan, Puerto Rico, USA cs Philadelphia FIGHT, 1233 Locust Street, 3rd Floor, Philadelphia, PA, USA ct ID Care, Hillsborough, NJ, USA cu Community Research Initiative of New England, Boston, USA cv Triple O Research Institute PA, West Palm Beach, FL, USA cw Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA cx Midway Immunology Center, Fort Pierce, FL, USA cy Capital Medical Associates, Washington, DC, USA cz Broward General Medical Center, Fort Lauderdale, FL, USA da Ruane Clinical Research Group, Los Angeles, CA, USA db Pacific Oaks Medical Group, Beverly Hills, CA, USA dc DCOL Center for Clinical Research, Longview, TX, USA dd Peter Shalit MD and Associates, 901 Boren Avenue, Suite 850, Seattle, WA, 98104, USA de La Playa Medical Group, San Diego, CA, USA df Department of Infectious Diseases, Seton Hall University, NJ, USA dg The Miriam Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA dh AIDS Arms, Inc., Dallas, TX, USA di Dupont Circle Physicians Group, Washington, DC, USA dj Wake Forest School of Medicine, Winston-Salem, NC, USA dk Living Hope Foundation, Long Beach, CA, USA ARTICLE INFO ABSTRACT Meetings at which parts of the data were Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated presented: Week 96 data were presented in part through 96 weeks in EMERALD (NCT02269917). at ID Week, October 3–7, 2018, in San Virologically-suppressed, HIV-1-positive treatment-experienced adults (previous non-darunavir virologic Francisco, CA, USA (abstract 1768). failure [VF] allowed) were randomized (2:1) to D/C/F/TAF or boosted protease inhibitor (PI) plus em- tricitabine/tenofovir-disoproxil-fumarate (F/TDF) over 48 weeks. At week 52 participants in the boosted PI arm Keywords: were offered switch to D/C/F/TAF (late-switch, 44 weeks D/C/F/TAF exposure). All participants were followed Darunavir/cobicistat/emtricitabine/TAF on D/C/F/TAF until week 96. Efficacy endpoints were percentage cumulative protocol-defined virologic re- Single-tablet regimen Safety bound (PDVR; confirmed viral load [VL] ≥50 copies/mL) and VL < 50 copies/mL (virologic suppression) and Efficacy ≥50 copies/mL (VF) (FDA-snapshot analysis). Switch study Of 1141 randomized patients, 1080 continued in the extension phase. Few patients had PDVR (D/C/F/TAF: 3.1%, 24/763 cumulative through week 96; late-switch: 2.3%, 8/352 week 52–96). Week 96 virologic sup- pression was 90.7% (692/763) (D/C/F/TAF) and 93.8% (330/352) (late-switch). VF was 1.2% and 1.7%, re- spectively. No darunavir, primary PI, tenofovir or emtricitabine resistance-associated mutations were observed post-baseline. No patients discontinued for efficacy-related reasons. Few discontinued due to adverse events (2% D/C/F/TAF arm). Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the late-switch arm, with small increases in total cholesterol/high-density-lipoprotein-cholesterol ratio. A study limitation was the lack of a control arm in the week 96 analysis. Through 96 weeks, D/C/F/TAF resulted in low PDVR rates, high virologic suppression rates, very few VFs, and no resistance development. Late-switch results were consistent with D/C/F/TAF week 48 results. EMERALD week 96 results confirm the efficacy, high genetic barrier to resistance and safety benefits of D/C/F/TAF. 1. Introduction Product Characteristics, 2017; Prescribing information for SYMTUZA™, 2018). For long-term virologic success in the treatment of HIV-1 infection, The primary 48-week analyses of the phase 3 AMBER sustained efficacy, long-term safety, tolerability, a high genetic barrier (NCT02431247) (Eron et al., 2018) and EMERALD (NCT02269917) to resistance and convenience are important considerations, given the (Orkin et al., 2018) trials showed that D/C/F/TAF had high, non-in- prolonged time individuals will receive antiretroviral treatment (ART). ferior antiviral efficacy with more favorable renal and bone safety Since the approval of boosted darunavir (DRV) in 2006, a wealth of versus D/C plus emtricitabine/tenofovir disoproxil fumarate (F/TDF) in clinical trial data and clinical experience has been generated, which ART-naïve adults in AMBER (Eron et al., 2018) and versus boosted demonstrates its high, durable virologic response, high genetic barrier protease inhibitor (bPI) plus F/TDF in ART-experienced, virologically to resistance, and long-term safety in a broad range of patients (Cahn suppressed adults in EMERALD (Orkin et al., 2018). et al., 2011; Eron et al., 2018; Flynn et al., 2014; Lathouwers et al., Treatment guidelines include the D/C/F/TAF STR or DRV boosted 2017; Orkin et al., 2013, 2018). with ritonavir or cobicistat combined with 2 nucleoside or nucleotide Once-daily, single-tablet HIV-1 treatment regimens (STRs) are pre- analogs reverse transcriptase inhibitors (N(t)RTIs) as a recommended ferred by patients and improve treatment adherence and satisfaction, treatment option (EACS, 2018) or recommend in certain clinical si- potentially reducing the rate of virologic failure (VF) and emergence of tuations, such as for those patients who may have uncertain adherence, antiretroviral resistance, resulting in a higher probability of long-term those who require a regimen with a high genetic barrier to resistance, viral load (VL) suppression, compared with multi-tablet regimens (Clay or those patients who may not have resistance results available (Panel et al., 2015; Nachega et al., 2011; Sterrantino et al., 2012). A once- on Antiretroviral Guidelines for Adults and Adolescents, updated July daily, STR combining darunavir with cobicistat, emtricitabine, and te- 10, 2019; Saag et al., 2018). nofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg, was recently A predefined week 96 analysis of the efficacy and safety of D/C/F/ approved in the US, EU, and Canada (SYMTUZA™ tablets Summary of TAF in the EMERALD clinical trial is presented. 3 J.J. Eron, et al. Antiviral Research 170 (2019) 104543 Abbreviations DRV darunavir F/TDF emtricitabine/tenofovir-disoproxil-fumarate AE adverse event N(t)RTI nucleoside(tide) analog reverse transcriptase inhibitor ART antiretroviral treatment PDVR protocol-defined virologic rebound BMD bone mineral density PI protease inhibitor bPI boosted protease inhibitor RAM resistance-associated mutation CI confidence interval STR single-tablet HIV-1 treatment regimen CKD-EPI Chronic Kidney Disease Epidemiology Collaboration VF virologic failure D/C/F/TAF darunavir/cobicistat/emtricitabine/tenofovir alafena- VL viral load mide 2. Material and methods 2.2. Study endpoints 2.1. Study design and patients The primary endpoint was protocol-defined virologic rebound (PDVR), defined as the proportion of patients with confirmed VL ≥ 50 Detailed methods for EMERALD (TMC114IFD3013) have been copies/mL or premature discontinuations irrespective of reason with previously reported (Orkin et al., 2018). Briefly, EMERALD is a phase 3, last VL ≥ 50 copies/mL, cumulative through week 48 in each arm. randomized, active-controlled, open-label, non-inferiority study con- Secondary efficacy endpoints were cumulative PDVR from baseline ducted at 106 sites across 9 countries. The study included ART-ex- through week 96 in the D/C/F/TAF arm and cumulative PDVR from perienced, HIV-1-positive adults who were virologically suppressed week 52 through week 96 in the late switch arm, and virologic outcome (VL < 50 copies/mL for ≥ 2 months before screening; one VL 50–200 at week 96 (VL < 50 and ≥ 50 copies/mL [VF]; FDA-snapshot ana- copies/mL within 12 months prior to screening was allowed) on stable lysis) in all randomized participants in the D/C/F/TAF arm and based bPI (DRV/ritonavir or DRV/cobicistat once daily, atazanavir/ritonavir on only those who switched in the boosted PI arm, comprising 44 weeks or atazanavir/cobicistat once daily, or lopinavir/ritonavir twice daily) of D/C/F/TAF exposure. Efficacy endpoints were also evaluated at the plus F/TDF regimens for ≥ 6 months. Previous non-DRV VF was al- 200 copies/mL cutoff. lowed. If historical genotypes were available, absence of DRV re- Other secondary endpoints included change in CD4+ cell count, sistance-associated mutations (RAMs) was required in line with the post-baseline HIV-1 genotypic resistance (GenoSure MG) in PDVRs with DRV once daily indication. VL ≥ 400 copies/mL at failure (preferably at confirmed rebound), at The trial consisted of a 48-week treatment period during which later post-rebound time points or at discontinuation, adherence to patients were randomized (2:1) to switch to the once daily D/C/F/TAF treatment based on drug accountability, adverse event (AE) incidences, 800/150/200/10 mg STR or continue on a bPI combined with F/TDF. changes in serum creatinine, estimated glomerular filtration rate based Patients could then continue on D/C/F/TAF (D/C/F/TAF arm) or on serum creatinine (eGFRcr, Chronic Kidney Disease Epidemiology switch from bPI plus F/TDF to D/C/F/TAF at week 52 (late switch arm, Collaboration [CKD-EPI] [Laterza et al., 2002]) and eGFR based on 44 weeks of D/C/F/TAF exposure) in an extension phase until week 96, cystatin C (eGFRcyst, CKD-EPI formula [Laterza et al., 2002; Levey et al., with study visits every 12 weeks. After week 96 participants were given 2009]), and ratios of total urine protein, urine albumin, retinol binding the opportunity to remain in the trial until the study drug became protein, and β-2-microglobulin to creatinine (UPCR, UACR, RPB:Cr and commercially available. B2M:Cr, respectively). Retrospectively, HIV-1 proviral DNA was se- quenced from baseline samples (VL < 50 copies/mL) to assess the Fig. 1. Patient disposition for EMERALD through 96 weeks. 4 J.J. Eron, et al. Antiviral Research 170 (2019) 104543 prevalence of archived RAMs in patients with prior VF. BMD. Reference for the D/C/F/TAF arm was baseline. Reference for the Endpoints in the bone investigation substudy were percentage late switch arm was the last value before the switch. change in hip, lumbar spine, and femoral neck bone mineral density (BMD) measured by DXA scans, changes in associated T-score (normal 3. Results BMD defined as a T-score ≥ −1; osteopenia as a T-score from ≥ −2.5 to < −1; and osteoporosis as a T-score < −2.5), and changes in bone 3.1. Patient baseline characteristics and disposition biomarkers. Overall (N = 1141) demographic and disease characteristics at 2.3. Statistical analysis baseline have been previously described (Orkin et al., 2018) (Supplementary Table 2). Median age was 46 years and most were male The main outcome analysis for the D/C/F/TAF arm was based on (82%), white (75%), and receiving boosted DRV (70%) at screening. the intent-to-treat population, which included all randomized patients Median (IQR) time since HIV diagnosis was 9.3 (4.2–18.1) years. who received at least 1 dose of study drug. For the control arm, the Overall, previous ART (including screening ART and PI booster counted week 96 analysis was based on patients who switched at week 52. A as a separate antiretroviral) included: ≥8 antiretrovirals (27% [312/ per-protocol analysis was also performed, which excluded patients with 1141]); ≥5 antiretrovirals (58%), ≥2 PIs (41%), ≥3 N(t)RTIs (42%), major protocol violations or other predefined criteria that potentially ≥1 non-nucleoside reverse transcriptase inhibitor (NNRTI) (30%), and affected the efficacy outcome (Supplementary Table 1). ≥1 integrase inhibitor (6%). Overall, 169 (15%) patients had previous Data analysis was performed using SAS software (SAS Institute, Inc, antiretroviral VF (7% on a PI, 11% on an N(t)RTI, 6% on an NNRTI, and Cary, NC, USA) version 9.2. Least squares mean change from reference 1% on an integrase inhibitor). in CD4+ cell count (non-completer equaled failure; last observation was Of 1141 patients randomized and treated, 1087/1141 patients carried forward otherwise) and associated 95% confidence intervals (95%) completed 48 weeks, and 1080 patients (95%) continued in the (CIs) were evaluated with ANCOVA, including a term for bPI used at extension phase (N = 728 D/C/F/TAF [95%]; N = 352 late switch screening and reference CD4+ count value as a covariate, fit separately [93%]) with 1036 patients (91%) ongoing on study treatment through for each treatment arm. Within treatment arm comparisons for change 96 weeks (Fig. 1). From week 48 through 96 weeks, the most common at week 96 from reference were assessed by Wilcoxon signed-rank test reasons for discontinuation, as indicated by the investigator, were AEs, for eGFR, renal biomarkers and fasting lipids and by paired t-test for loss to follow-up and withdrawn consent (Fig. 1) with a similar Fig. 2. Protocol-defined virologic rebound (PDVR) through Week 96; A) ≥50 copies/mL and B) ≥200 copies/mL. *Two-sided Exact Clopper-Pearson 95% confidence interval (CI); †Comprising 44 weeks of D/C/F/TAF exposure. 5 J.J. Eron, et al. Antiviral Research 170 (2019) 104543 proportion between arms (4%). suppressed (VL < 50 copies/mL; FDA-snapshot analysis) at week 96. 3.2. Efficacy analyses 3.3. Immunologic response Few patients had PDVR (VL ≥ 50 copies/mL) cumulative through The least squares mean (95% CI) increase from baseline in CD4+ week 96 in the D/C/F/TAF arm (3.1%, 24/763) (Fig. 2A). In the late cell count to week 96 was 32.1 (95% CI: 16.4 to 47.8) cells/mm3 in the switch arm, PDVR occurred in 2.3% of patients (8/352) from week 52 D/C/F/TAF arm. In the late switch arm, the increase from the last value through week 96 (Fig. 2A). Of the patients with PDVR, 14/24 in the D/ prior to switch to week 96 was 13.1 (95% CI: -8.0 to 34.1) cells/mm3. C/F/TAF arm through week 96 and 2/8 in the late switch arm from week 52 through week 96 resuppressed by week 96 while maintaining D/C/F/TAF therapy (Fig. 2A). There were 4/763 (0.5%) PDVRs 3.4. Resistance analysis (VL ≥ 200 copies/mL) in the D/C/F/TAF arm cumulative through week 96 and 2/352 (0.6%) over 44 weeks in the late switch arm (Fig. 2B). Few patients had PDVR cumulative through 96 weeks, with most PDVR (VL ≥ 50 copies/mL) cumulative through week 96 was con- having low VL values throughout the study, so very few samples were sistent using the per-protocol analysis (Supplementary Table 3). eligible for genotyping (HIV-1 RNA ≥ 400 copies/mL at rebound or at Through 96 weeks, no patient in the D/C/F/TAF arm discontinued later time points). Through week 96, 4 out of 24 rebounders in the D/C/ dosing due to loss of virologic efficacy. F/TAF arm had post-baseline genotype data, and 2 out of 8 rebounders At week 96, VL ≥ 50 copies/mL (FDA-snapshot analysis) occurred in the late switch arm had genotype data after week 52. No DRV, pri- in 9/763 (1.2%) patients in the D/C/F/TAF arm and in 6/352 (1.7%) mary PI, tenofovir or emtricitabine RAMs (Wensing et al., 2014) were patients in the late switch arm (Fig. 3A and Supplementary Table 4). A observed post baseline. All patients had HIV-1 virus susceptible to all high proportion of patients in the D/C/F/TAF arm (90.7%, 692/763) drugs in the regimens. One patient in the D/C/F/TAF arm had a sec- and late switch arm (93.8%, 330/352) had a VL < 50 copies/mL (FDA- ondary PI RAM L63P and an NNRTI RAM K103N, conferring resistance snapshot analysis) at week 96 (Fig. 3A and Supplementary Table 4). Of to efavirenz (EFV) and nevirapine, which was probably related to those who were < 50 copies/mL at week 48, 95.2% (689/724) (D/C/F/ previous virologic failure of EFV/F/TDF and previous use of nevirapine. TAF arm) and 93.7% (328/350) (late switch arm) maintained virologic suppression at week 96. Virologic responses were consistent with the FDA-snapshot analysis using the VL < 200 copies/mL cutoff (Fig. 3B 3.5. Adherence to treatment and Supplementary Table 4) and the per-protocol < 50 copies/mL FDA- snapshot analysis (Supplementary Table 3). Median (IQR) cumulative adherence to the end of week 96, as PDVR and FDA-snapshot outcomes were consistent across the measured by pill count, was 99.7% (98.2%; 100.2%) in patients in the baseline patient subgroups, sex, age, race, previous antiretroviral use, D/C/F/TAF arm. Median (IQR) cumulative adherence was 99.2% and previous antiretroviral VF (Supplementary Table 5). In the D/C/F/ (96.9%; 100.0%) from baseline to week 52 and 99.7% (97.4%, 100.0%) TAF arm, of the 116 patients with ≥1 previous antiretroviral VF, PDVR from week 52 to week 96 in the late switch arm. occurred in 4.3% of patients (5/116) and 87.1% (101/116) were Fig. 3. FDA-snapshot analysis at weeks 48 and 96; A) < 50 copies/mL and B) < 200 copies/mL. *Two-sided Exact Clopper-Pearson 95% confidence interval (CI); †Last VL in week 48 or week 96 window ≥ 50 copies/mL, or discontinuation for ef- ficacy reasons, or premature discontinuations (not due to efficacy, adverse events or death), with last (single) VL ≥ 50 copies/mL; ‡Last VL in week 48 or week 96 window ≥ 200 copies/mL, or discontinua- tion for efficacy reasons, or premature discontinua- tions (not due to efficacy, adverse events or death), with last (single) VL ≥ 200 copies/mL; §Late switch to D/C/F/TAF arm week 96 results are based on patients who switched to D/C/F/TAF at week 52 (comprising 44 weeks of D/C/F/TAF exposure). 6 J.J. Eron, et al. Antiviral Research 170 (2019) 104543 3.6. Safety and tolerability arms) through week 96 were upper respiratory tract infection, viral upper respiratory tract infection, diarrhea and headache. D/C/F/TAF was well tolerated with 9% [66/763] serious AEs and Most AEs, irrespective of causality, were grade 1 or 2. The most 2% [17/763] AE-related discontinuations through 96 weeks in the D/ common grade 3 AE in the D/C/F/TAF arm was increased low-density C/F/TAF arm of which 5% (36/728) and 1% (5/728), respectively, lipoprotein-cholesterol (LDL-C), which was reported for 2 patients be- occurred between weeks 48 and 96. In the late switch arm from week fore week 48 and 2 patients after week 48 (both < 1%), and in the late 52 through week 96, 6% [21/352] and 2% [7/352]) serious AEs and switch arm from week 52 through week 96, pneumonia, tendon rup- AE-related discontinuations occurred (Table 1). AEs at least possibly ture, hypercholesterolemia, and depression, each reported for 2 pa- related to study drug were reported in 22% [165/763] of patients in the tients (< 1%). Three cases of myocardial infarction (0.3%, 3/1080) D/C/F/TAF arm over 96 weeks, and in 11% [38/352] of patients over occurred after week 48, including 2 in the D/C/F/TAF arm and 1 in the 44 weeks of D/C/F/TAF treatment in the late switch arm. The most late switch arm. common AEs (all grades, ≥ 5% in both D/C/F/TAF and late switch Three deaths occurring after week 48 in the D/C/F/TAF arm were Table 1 Overview of treatment-emergent AEs and laboratory abnormalities and median (IQR) change from baseline in lipids at Week 96. D/C/F/TAF Arm Late Switch Arm D/C/F/TAF D/C/F/TAF (week D/C/F/TAF P-valueb,c bPI + F/TDF (baseline – D/C/F/TAFa (week P-valueb,c (baseline – week 48) 48 – week 96) (baseline – week 96) week 52) N = 378 52 –week 96) N = 763 N = 728 N = 763 N = 352 Patient years exposured 689 664 1353 366 295 Treatment-emergent AEs, n (%) AEs, any grade, regardless of 630 (83) 522 (72) 690 (90) ND 316 (84) 258 (73) ND causality Study drug-related AEs 144 (19) 37 (5) 165 (22) ND 28 (7) 38 (11) ND Grade 3–4 AEs regardless of 54 (7) 52 (7) 98 (13) ND 31 (8) 26 (7) ND causality Study drug-related Grade 3 or 4 10 (1) 6 (1) 14 (2) ND 4 (1) 7 (2) ND AEs Serious AEs regardless of causality 35 (5) 36 (5) 66 (9) ND 18 (5) 21 (6) ND Study drug-related serious AEs 1 (< 1) 1 (< 1) 2 (< 1) ND 0 1 (< 1) ND AE-related discontinuations 12 (2) 5 (1) 17e (2) ND 5 (1) 7e (2) ND Deaths 0 3f (< 1) 3f (< 1) ND 0 0 ND Most common AEs regardless of causality (≥10% D/C/F/TAF arm through 96 weeks) Upper respiratory tract infection 81 (11) 60 (8) 122 (16) ND 39 (10) 30 (9) ND Viral upper respiratory tract 72 (9) 34 (5) 98 (13) ND 40 (11) 25 (7) ND infection Diarrhea 60 (8) 26 (4) 80 (11) ND 18 (5) 16 (5) ND Headache 58 (8) 25 (3) 79 (10) ND 18 (5) 18 (5) ND Back pain 55 (7) 29 (4) 76 (10) ND 23 (6) 12 (3) ND Study drug-related AEs (all grades; ≥ 1% either arm) Diarrhea 16 (2) 1 (< 1) 17 (2) ND 2 (1) 4 (1) ND Headache 10 (1) 1 (< 1) 11 (1) ND 0 1 (< 1) ND Abdominal pain 11 (1) 0 11 (1) ND 0 0 ND Osteopenia 5 (1) 0 5 (1) ND 9 (2) 0 ND Most common treatment-emergent grade 3 or 4 laboratory abnormalities (> 5% either arm) Fasting LDL-C (≥4.90 mol/L; ≥ 47/737 (6) 38/688 (6) 67/741 (9) ND 6/364 (2) 9/328 (3) ND 190 mg/dL) Fasting total cholesterol 27/737 (4) 16/692 (2) 36/741 (5) ND 5/364 (1) 6/330 (2) ND (≥7.77 mol/L; ≥ 300 mg/dL) Median (IQR) change in fasting lipids TC (mg/dL) +19.9 (1.2; 39.4) ND +22.0 (−0.4; 44.0) < 0.001 +1.3 (−12.0; 20.0) +22.0 (3.0; 42.7) < 0.001 HDL-C (mg/dL) +2.7 (−3.0; 8.0) ND +3.0 (−2.0; 8.5) < 0.001 0.0 (−4.6; 4.0) +3.3 (−2.0; 8.0) < 0.001 LDL-C (mg/dL) +15.9 (0.0; 32.0) ND +17.0 (−3.0; 35.2) < 0.001 +1.9 (−12.0; 17.0) +15.0 (0.0; 32.9) < 0.001 Triglycerides (mg/dL) +5.7 (−21.0; 39.0) ND +7.0 (−25.0; 43.0) < 0.001 +4.9 (−23.0; 39.0) +8.0 (−25.8; 0.004 47.0) TC/HDL-C ratio +0.20 (−0.20; ND +0.20 (−0.40; < 0.001 +0.10 (−0.30; 0.40) +0.20 (−0.30; < 0.001 0.60) 0.70) 0.70) AEs, adverse events; IQR, interquartile range; TC, total cholesterol; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; ND, not determined. a Comprising 44 weeks of D/C/F/TAF exposure (i.e. from the switch to D/C/F/TAF at week 52). b Within treatment arm comparisons for change at week 96 from reference assessed by: Wilcoxon signed-rank test (eGFR, renal biomarkers and fasting lipids) and paired t-test (BMD). c Reference for the D/C/F/TAF arm is study baseline and for the late switchers is the last value before the switch. d Patient years of exposure = sum of treatment duration (in weeks) x 7/365.25. e D/C/F/TAF arm: abdominal pain, diarrhea, gastrooesophageal reflux disease, pancreatitis, alanine aminotransferase increased, blood corticotrophin decreased, cortisol decreased, Hodgkin's disease, lymphoma, anxiety, depression suicidal, insomnia, Cushing's syndrome, edema peripheral, headache, urticaria, flushing (n = 1 each); myocardial infarction (n = 2), chronic kidney disease (n = 2; worsening of pre-existing chronic kidney disease in one patient prior to week 48 (Orkin et al., 2018) and chronic kidney disease in a participant after week 48); D/C/F/TAF late switch arm: vertigo, Cushing's syndrome, diarrhea, nausea, vomiting, malaria, pregnancy, depression, rash (n = 1 each). f Three deaths were due to metastatic pancreatic carcinoma and 2 cases of myocardial infarction, 1 of which was in a patient who was a smoker, with an ongoing medical history of hyperlipidemia and hypertension and 1 was in a patient with an ongoing medical history of obesity and hypertension. 7 J.J. Eron, et al. Antiviral Research 170 (2019) 104543 due to metastatic pancreatic carcinoma and 2 cases of myocardial in- 4.6) kg versus baseline in the D/C/F/TAF arm and +1.6 (−0.4; 3.5) kg farction; 1 in a patient who was a smoker with an ongoing medical versus the value prior to switching in the late switch arm. history of hyperlipidemia and hypertension and 1 patient with an on- going medical history of obesity and hypertension. The only other serious AE deemed as possibly related to a study drug by the in- 3.6.1. Laboratory parameters vestigator and occurring after week 48 was grade 3 Cushing's syndrome Fasting lipid parameters remained stable after week 48 in the D/C/ in the late switch arm, which is likely explained by the administration F/TAF arm and increased from the value prior to switching to week 96 of intramuscular corticosteroid injections. in the late switch arm. The change in TC/HDL-C ratio from the value Renal AEs regardless of causality occurred in 3% (20/763) of pa- prior to switching in the late switch arm was +0.20, while the ratio in tients in the D/C/F/TAF arm over 96 weeks, and in 1% [5/352] of the D/C/F/TAF arm remained stable after week 48 (all changes patients in the late switch arm from week 52 through week 96. Two P < 0.005) (Table 1 and Supplementary Fig. 1). During treatment, grade 2, non-serious, related renal AEs led to discontinuation in the D/ lipid-lowering drugs were started by 32/763 (4%) and 59/763 (8%) of C/F/TAF arm over 96 weeks (Table 1 footnote). Neither renal AE met patients by weeks 48 and 96, respectively, in the D/C/F/TAF arm, and the criteria for proximal renal tubulopathy (PRT). No renal AEs led to by 3% (11/378) and 5% (19/352), respectively, in the control arm. discontinuation of D/C/F/TAF in the late switch arm or suggested In the D/C/F/TAF arm, median (IQR) change from baseline to week treatment-emergent PRT. 96 in eGFRcr was −1.3 (−8.3; 5.1) mL/min/1.73 m2 (Fig. 4A) Most treatment-emergent laboratory abnormality events were grade (P < 0.001). Median change from the value prior to switching to week 1 or 2. Only grade 3 or 4 fasting LDL-C occurred in ≥5% of patients in 96 in eGFRcr was −0.7 (−6.9; 4.9) mL/min/1.73 m2 in the late switch the D/C/F/TAF arm over 96 weeks (9% [67/741]) (Table 1) of which arm (P = 0.007) (Fig. 4A). Median changes in eGFRcyst were similar 6% (38/688) occurred after week 48. No events occurred in ≥5% of (Fig. 4B). patients in the late switch arm. In the D/C/F/TAF arm, improvements in renal biomarkers seen at Median (IQR) change in body weight at week 96 was +1.8 (−0.8; 48 weeks compared with baseline were maintained through week 96 (Supplementary Fig. 2A). Median (IQR) changes from baseline to week Fig. 4. Change from reference to week 48 and week 96 in renal and bone parameters. A) eGFRcyst, B) eGFRcr and BMD of the C) hip, D) lumbar spine, and E) femoral neck. *Comprising ~44 weeks of D/C/F/TAF exposure (i.e. from the switch to D/C/F/TAF at week 52). †Within treatment arm change from reference assessed by Wilcoxon signed-rank test (eGFR) and paired t-test (BMD). ‡Reference for D/C/F/TAF and control is baseline and for late switch (D/C/F/TAF) is the last value before the switch. 8 J.J. Eron, et al. Antiviral Research 170 (2019) 104543 96 were −22.2 (−51.5; −3.5) mg/g for UPCR, −0.6 (−3.7; 1.2) mg/g weeks was similar to week 96 response rates in other HIV studies for UACR, −25.1 (−106.4; 13.1) μg/g for RBP:Cr and −68.2 (−386.6; evaluating switching to integrase inhibitor-based regimens (Aboud −11.0) μg/g for B2M:Cr (all P < 0.001 vs. baseline). In the late switch et al., 2018; Gatell et al., 2019). arm, significant improvements at week 96 versus the value prior to PDVR and response rates should be placed in the context that these switching (all P < 0.001) were seen for median (IQR) changes in UPCR patients were treatment experienced, with 58% of patients having re- [–12.8 (−48.2; 6.4) mg/g], UACR [–0.9 (−6.0; 1.1) mg/g], RBP:Cr ceived ≥5 previous antiretroviral agents, and 15% having previous [–39.1 (−200.1; 4.3) μg/g] and B2M:Cr [–110.3 (−496.8; −18.3) μg/ antiretroviral VF. Previous antiretroviral use and VF did not affect g] (Supplementary Fig. 2A). PDVR and response rates. No patient developed resistance to any of the study drugs through 3.6.2. Bone substudy week 96 despite a cumulative 1648 patient-years of exposure to D/C/F/ The bone substudy included 209 patients in the D/C/F/TAF arm and TAF. This is consistent with previous DRV and D/C/F/TAF studies 108 in the control arm (Orkin et al., 2018). Over 96 weeks, there were (Eron et al., 2018; Lathouwers et al., 2017), further supporting the high sustained improvements in BMD at the hip (+1.85% at week 96 vs. genetic barrier to resistance of DRV. baseline; Fig. 4C), lumbar spine (+2.00%; Fig. 4D), and femoral neck D/C/F/TAF was generally well tolerated through 96 weeks, with (+1.38%; Fig. 4E) in the D/C/F/TAF arm (all P < 0.001 vs. baseline, low incidences of discontinuations due to AEs (2%) that were numeri- paired t-test). Similar significant improvements in BMD at week 96 cally lower than incidences seen in integrase inhibitor-based regimen compared with the value prior to switching were seen in the late switch switching studies over 96 weeks (Aboud et al., 2018; Gatell et al., arm (Fig. 4C‒E). 2019). The D/C/F/TAF tolerability profile at week 96 was consistent In the D/C/F/TAF arm, the proportion of patients who had a ≥3% with the week 48 analyses of EMERALD (Orkin et al., 2018) and decrease or increase in hip, lumbar spine, and femoral neck BMD at AMBER (Eron et al., 2018). week 96 versus baseline was stable through week 96 (Supplementary The small increase in body weight in the D/C/F/TAF arm over 2 Table 6). In the late switch arm, more patients had a ≥3% increase in years (1.8 kg) is consistent with previous studies of patients receiving BMD at each site over 44 weeks of D/C/F/TAF treatment than over the ART (Taramasso et al., 2017), and may be due in part to lifestyle first 48 weeks of bPI plus F/TDF therapy, and fewer patients had a changes and improved disease control. Weight gains were numerically ≥3% decrease in BMD (Supplementary Table 6). Conclusions were si- larger over 9–18 months when switching to integrase inhibitor-based milar for increases or decreases of ≥5% or ≥7% in BMD, as well for the ART, particularly for dolutegravir (Menard et al., 2017; Norwood et al., proportions of patients with an improvement (osteopenia to normal or 2017). osteoporosis to normal or osteopenia) or a decline (normal to osteo- Renal, bone, and lipid safety were consistent with the established penia or normal or osteopenia to osteoporosis) in BMD clinical status effects of TAF versus TDF and cobicistat (DeJesus et al., 2018; Eron (Supplementary Table 6). et al., 2018; Orkin et al., 2018; Raffi et al., 2017; Wohl et al., 2016). Changes in bone biomarkers overs weeks 52–96 in the late switch Small decreases in eGFRcr in both arms were well within normal limits arm were similar to those reported by week 48 in the D/C/F/TAF arm and possibly due to the effect of cobicistat on inhibition of tubular se- (Supplementary Fig. 2B). cretion of creatinine without reducing actual GFR (Elion et al., 2011; Gallant et al., 2013; German et al., 2012). When measuring GFR with 4. Discussion cystatin C, which is not affected by the interaction of cobicistat with creatinine secretion (Laterza et al., 2002), changes were also small, The week 96 analysis of this phase 3, randomized, open-label trial with all results remaining within normal limits. showed that a low proportion of treatment-experienced, virologically Improvements in renal tubular proteinuria and bone parameters suppressed HIV-1-positive adults in the D/C/F/TAF arm had PDVR were maintained in the D/C/F/TAF arm and seen in the late switch arm (≥50 copies/mL) cumulative through 96 weeks (3.1%) and a high from week 52 to week 96, suggesting that D/C/F/TAF has a lower proportion (90.7%) remained suppressed (VL < 50 copies/mL) at potential for nephrotoxicity and bone loss than the control regimen. week 96, with few patients (1.2%) having VL ≥ 50 copies/mL (FDA- These renal tubular proteinuria and bone safety results are consistent snapshot analysis). Virologic rebound mainly consisted of low-level and with the week 48 results in the D/C/F/TAF arm of EMERALD (Orkin transient viremia, with very few PDVRs ≥200 copies/mL (0.5%). More et al., 2018) and AMBER (Eron et al., 2018) and week 96 analyses of than half of patients in the D/C/F/TAF arm with PDVR ≥50 copies/mL previous phase 3 studies in virologically suppressed patients who achieved resuppression by week 96, without a change in therapy. In the switched from a TDF- to a TAF-containing regimen (DeJesus et al., late switch arm, only 2.3% had PDVR cumulative through 44 weeks, 2018; Raffi et al., 2017; Wohl et al., 2016), including a pooled analysis and virologic suppression was also sustained at week 96 (93.8%) with of 5 phase 3 studies (Rockstroh et al., 2017). 1.7% of patients having VL ≥ 50 copies/mL (FDA snapshot), consistent In the D/C/F/TAF arm, fasting lipid levels remained stable after with week 48 results in the D/C/F/TAF arm. Importantly, through week week 48 with minimal increases in the late switch arm and an identical 96 no patients needed to discontinue D/C/F/TAF due to lack of efficacy. change in TC/HDL-C ratio (+0.2) in both arms at week 96. Only a small Results were consistent across baseline patient subgroups, in the per- proportion of patients initiated lipid-lowering therapy in both arms. protocol PDVR and FDA-snapshot analyses and using the 200 copies/ A study limitation was the lack of a control arm in the week 96 mL cutoff. analysis, as patients in both arms were switched to D/C/F/TAF. Other While considering differences in study designs when making com- limitations, as at week 48, include the lack of power to assess efficacy in parisons, entry criteria were less restrictive than in other switch studies patient subgroups and assessment of bone parameters in only a subset with comparable or lower response rates e.g. for bictegravir (Daar et al., of participants. 2018; Molina et al., 2018), dolutegravir (Joly et al., 2017; Llibre et al., In conclusion, in virologically suppressed, treatment-experienced, 2018; Taiwo et al., 2018; Trottier et al., 2017), and atazanavir (Di HIV-positive adults, including those with prior VF and archived re- Giambenedetto et al., 2017; Perez-Molina et al., 2015). In EMERALD, sistance, switching to the D/C/F/TAF STR resulted in low PDVR rates there was no exclusion based on previous VF or RAMs, except for his- cumulative through 96 weeks (3% D/C/F/TAF; 2% late switch) and tory of VF on DRV-based regimens or DRV RAMs if historical genotypes maintenance of high virologic suppression rates (> 90%) at week 96. were available. However, it should be noted only ≥3 DRV RAMs is Efficacy and safety results in the late switch arm were consistent with correlated with DRV resistance (de Meyer et al., 2008). N(t)RTI RAMs, week 48 results in the D/C/F/TAF arm. No patients discontinued for including emtricitabine or tenofovir RAMs, were not an exclusion cri- efficacy-related reasons, and no drug resistance mutations developed. terion. The proportion of patients achieving VL < 50 copies/mL at 96 D/C/F/TAF was well tolerated over 96 weeks with bone, renal and lipid 9 J.J. Eron, et al. Antiviral Research 170 (2019) 104543 safety consistent with known profiles of the D/C/F/TAF components. company, Macclesfield, UK) for assistance in drafting the manuscript Results of EMERALD through 96 weeks confirm the efficacy, high ge- and coordinating and collating author contributions, which was funded netic barrier to resistance and safety advantages of D/C/F/TAF, even in by Janssen. The data sharing policy of Janssen Pharmaceutical patients with a history of non-DRV VF. Companies of Johnson & Johnson is available at https://www.janssen. com/clinical-trials/transparency. As noted on this site, requests for Sources of funding access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu. This study was sponsored by Janssen. Appendix A. Supplementary data Contributors Supplementary data to this article can be found online at https:// JJE, CO, DC, F Pulido, F Post and SDW were investigators in the trial doi.org/10.1016/j.antiviral.2019.104543. and reported data for those patients. EL, VH, RP, KB and EVL were involved in the data analyses. All authors were involved in the devel- References opment of the primary manuscript, interpretation of data, and have read and approved the final version, and have met the criteria for au- Aboud, M., Orkin, C., Podzamczer, D., Bogner, J., Baker, D., Khuong-Josses, M.-.A., Parks, thorship as established by the ICMJE. D., Angelis, K., Kahl, L., Blair, E., Underwood, M., Wynne, B., Vandermeulen, K., Gartland, M., Smith, K., 2018. In: Durable Suppression 2 Years after Switch to DTG+RPV 2-Drug Regimen: SWORD 1&2 Studies. 22nd International AIDS EMERALD principal investigators Conference (AIDS 2018), July 23–27, 2018, Amsterdam, The Netherlands, Abstract and poster THPEB047. 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Version 9.1. http:// J.J.E. has received research grants from Janssen, Gilead Sciences www.eacsociety.org/files/2018_guidelines-9.1-english.pdf Accessed July 12, 2019. and ViiV Healthcare and has served as a consultant to BMS, Merck, Elion, R., Cohen, C., Gathe, J., Shalit, P., Hawkins, T., Liu, H.C., Mathias, A.A., Chuck, Janssen, Gilead Sciences and ViiV Healthcare. C.O. has received S.L., Kearney, B.P., Warren, D.R., GS-US-216-0105 Study Team, 2011. Phase 2 study speaker honoraria or consulting fees for attending speakers’ bureaus or of cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose em- tricitabine/tenofovir DF in the initial treatment of HIV infection. AIDS 25, advisory boards and research grants from Janssen, Merck, ViiV 1881–1886. Healthcare, and Gilead Sciences. D.C. has received research grants from Eron, J.J., Orkin, C., Gallant, J., Molina, J.M., Negredo, E., Antinori, A., Mills, A., Reynes, Janssen, Merck, ViiV Healthcare and Gilead Sciences. F. Pulido has J., Van Landuyt, E., Lathouwers, E., Hufkens, V., Jezorwski, J., Vanveggel, S., Opsomer, M., AMBER study group, 2018. A week 48 randomized phase 3 trial of received speaker honoraria or consulting fees for attending advisory darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naïve HIV-1 boards and research grants from Janssen, Merck, ViiV Healthcare, and patients. AIDS 32, 1431–1442. Gilead Sciences. F. Post has received consulting fees from Gilead Flynn, P., Komar, S., Blanche, S., Giaquinto, C., Noguera-Julian, A., Welch, S., Lathouwers, E., Van de Casteele, T., Kakuda, T.N., Opsomer, M., 2014. Efficacy and Sciences, Janssen, ViiV Healthcare and Merck and research grants from safety of darunavir/ritonavir at 48 weeks in treatment-naïve, HIV-1-infected ado- Gilead Sciences and ViiV Healthcare. S.D.W. has received consulting lescents: results from a phase 2 open-label trial (DIONE). Pediatr. Infect. Dis. J. 33, fees for attending advisory boards and research grants from Janssen, 940–945. Gallant, J.E., Koenig, E., Andrade-Villanueva, J., Chetchotisakd, P., DeJesus, E., Antunes, Merck, ViiV Healthcare and Gilead Sciences. E.L., V.H., K.B., and E.V.L. F., Arastéh, K., Moyle, G., Rizzardini, G., Fehr, J., Liu, Y., Zhong, L., Callebaut, C., are all full-time employees of Janssen and potential stockholders of Szwarcberg, J., Rhee, M.S., Cheng, A.K., 2013. Cobicistat versus ritonavir as a Johnson and Johnson. R.P. was a contractor for Janssen. pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results. J. Infect. Dis. 208, 32–39. Acknowledgments Gatell, J.M., Assoumou, L., Moyle, G., Waters, L., Johnson, M., Domingo, P., Fox, J., Martinez, E., Stellbrink, H.J., Guaraldi, G., Masia, M., Gompels, M., De Wit, S., We thank the patients and their families for their participation and Florence, E., Esser, S., Raffi, F., Stephan, C., Rockstroh, J., Giacomelli, A., Vera, J., Bernardino, J.I., Winston, A., Saumoy, M., Gras, J., Katlama, C., Pozniak, A.L., support during the study, the central and local Janssen EMERALD study European Network for AIDS Treatment 022 (NEAT022) Study Group, 2019. teams, study center staff, and the principal investigators. We also thank Immediate vs. deferred switching from a boosted protease inhibitor (PI/r) based re- other Janssen staff members for their input into this manuscript. 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