Study Designs

Treatment-naïve adults

AMBER: Phase 3, randomized, double-blind, active-controlled, international, multicenter, noninferiority study1-3

  • After Week 48, patients could continue on or switch to SYMTUZA® in an open-label, single-arm extension phase until Week 96

Primary endpoint: Proportion of patients with VL <50 copies/mL at 48 weeks (noninferiority margin 10% by FDA Snapshot).

Virologically suppressed adults

EMERALD: Phase 3, randomized, open-label, international, multicenter, noninferiority study4,5

  • Patients had been on therapy ≥6 months with no history of virologic failure on darunavir-based regimens and were virologically suppressed prior to and at screening
  • After Week 48, patients could continue on or switch to SYMTUZA® in an open-label extension phase until Week 96

Key endpoints: Proportion of patients with virologic rebound at Week 48 (noninferiority margin 4%); Proportion of patients with VL <50 copies/mL at 48 weeks (FDA Snapshot).

Rapid initiation

DIAMOND: Phase 3, open-label, single-arm, multicenter, prospective study of treatment-naïve adults6,7

  • Patients were newly diagnosed within 14 days of beginning treatment and were ARV-naïve, except for potential prior use of FTC/TDF for PrEP
  • Screening/baseline safety laboratory findings were evaluated on Day 3 (+1 week),†‡ and resistance was evaluated at Week 4 (±7 days)§ based on predicted genotypic sensitivity

Key endpoints were: 

  • Proportion of patients with VL <50 copies/mL at 48 weeks (ITT, FDA Snapshot)
  • Proportion of patients with VL <50 copies/mL or <200 copies/mL at 48 weeks (observed analysis)
  • Descriptive statistics for absolute values in HIVTSQs scores were calculated for each question, for each subscale, and overall at 48 weeks

Prior to or when initiating SYMTUZA®, patients should undergo testing for HBV and renal function. Appropriate labs, including liver testing, hepatitis serology, and HIV genotypic resistance testing should be conducted and patients monitored during treatment as clinically appropriate.2

 

DIAMOND was not a pivotal registrational trial. AMBER was the pivotal registrational trial which studied treatment-naïve patients.1

*Randomization was stratified by VL and CD4+ cell count.1

Evaluations could be done sooner based on availability of results.7

Screening/baseline safety laboratory findings were evaluated with the following stopping criteria (retesting of abnormal screening/baseline safety laboratory values was allowed once): eGFR (MDRD formula) <50 mL/min, AST or ALT ≥2.5 times the ULN, serum lipase ≥1.5 times the ULN, positive pregnancy test for women of childbearing potential, laboratory results that the investigator believes should result in discontinuation of study medication, or active hepatitis C infection that, in the opinion of the investigator, required immediate treatment or was expected to require treatment during the study with agents not compatible with the components of SYMTUZA®.7

§Resistance was evaluated based on predicted genotypic sensitivity (there was no exclusion based on the presence of specific RAMs). Patients who did not show full genotypic sensitivity to the components of SYMTUZA® (assessed using GenoSure Prime®) were stopped; an exception was resistance to lamivudine/emtricitabine associated with the M184I/V mutation alone.6

Virologic Suppression Achieved at Week 48 and Maintained at Week 96

Virologic response rates (FDA Snapshot)

treatment_naive_mob

  • 4% virologic failure rate (≥50 copies/mL) in the SYMTUZA® arm vs 3% in the control arm at 48 weeks3
    • 6% virologic failure rate in the SYMTUZA® arm at 96 weeks
  • 4% of patients in the SYMTUZA® arm had no virologic data at 48 weeks vs 8% in the control arm3
    • 9% of patients in the SYMTUZA® arm had no virologic data at 96 weeks

*Week 96 was an open-label, single-arm extension, not the primary endpoint.3,4

  • 1% virologic failure rate (≥50 copies/mL) in the SYMTUZA® arm vs 1% in the control arm at 48 weeks5
    • 1% virologic failure rate in the SYMTUZA® arm at 96 weeks4
  • 4% of patients in the SYMTUZA® arm had no virologic data at 48 weeks vs 6% in the control arm5
    • 8% of patients in the SYMTUZA® arm had no virologic data at 96 weeks4

Consistent Virologic Response Regardless of Baseline Neuropsychiatric Comorbidities

Post hoc subgroup analysis: virologic response rates in treatment-naïve patients at 48 weeks8*

  • Among participants with baseline NPCs, none experienced virologic failure leading to discontinuation8
  • No participants discontinued due to a lack of efficacy or developed darunavir, primary protease inhibitor, or tenofovir resistance-associated mutations8
  • In the total population, there was a 4% virologic failure rate (≥50 copies/mL) in the SYMTUZA® arm vs 3% in the control arm3

*Among 725 patients, 88 (SYMTUZA®) and 99 (control) had baseline NPCs.8

In the SYMTUZA® arm, 43% (38/88) had neurologic comorbidities, such as headache (20%) or migraine (6%). In the control arm, 43% (43/99) had neurologic comorbidities, such as headache (21%) or migraine (8%).8

In the SYMTUZA® arm, 64% (56/88) had psychiatric comorbidities, such as depression (35%), anxiety (18%), or insomnia (7%). In the control arm, 70% (69/99) had psychiatric comorbidities, such as depression (27%), anxiety (14%), or insomnia (13%).8

The Only Evidence-Based STR Recommended by the DHHS Guidelines for Rapid Initiation

of patients (N=109) discontinued due to adverse events over 48 weeks6

discontinuations due to diarrhea or CNS adverse events6

  • Only one patient discontinued due to adverse events6
    • This patient had allergic dermatitis (Grade 3), pyrexia (Grade 2), and lip swelling (Grade 2)
    • All adverse events resolved after discontinuation of study treatment

across multiple sub-populations, including MSM, Black, Hispanic, and 18 to 25 years old9

8% of patients had virologic failure (≥50 copies/mL) and 7% had no VL data6

  • No patients had protocol-defined virologic failure, and there were no study discontinuations due to lack of efficacy

*Observed=patients with missing data were excluded from the analysis.6

Observed analysis: 96% of MSM (n=74), 97% of Black/African American (n=30), 95% of Hispanic (n=44), 100% of 18 to 25 years old (n=32), and 90% of women (n=10) achieved VL <50 copies/mL at Week 48.

ITT, FDA Snapshot analysis: 87% of MSM (n=82), 83% of Black/African American (n=35), 88% of Hispanic (n=48), and 84% of 18 to 25 years old (n=38) achieved VL <50 copies/mL at Week 48.9

Lift the Virologic Burden With Proven Efficacy and Resistance Protection

In a study of virologically suppressed patients

95-percent

of patients were undetectable (VL <50 copies/mL) at Week 48 vs 94% in the control arm5

  • 1% VF rate in the SYMTUZA® arm vs 1% in the control arm5*
    • There were no discontinuations due to lack of efficacy5
  • 4% of patients in the SYMTUZA® arm had no virologic data vs 6% in the control arm5

15-percent

of patients in the SYMTUZA® arm (n=116/763) had prior VF on at least one ARV5

  • Prior VF did not impact treatment outcomes2

100-percent

of patients across both treatment arms with archived emtricitabine RAMs (n=53), mainly at reverse transcriptase position M184, maintained virologic suppression at Week 48 or at latest time point assessed2

*Included patients who had ≥50 copies/mL in the 48-week window; patients who discontinued early due to lack or loss of efficacy; patients who discontinued for reasons other than adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value ≥50 copies/mL.5

SYMTUZA®: Because the Need to Defend Against Resistance Never Ceases

treatment-emergent mutations in rapid initiation6*

The protective barrier of darunavir was studied in >5500 patients in 14 clinical trials with data up to 192 weeks2,6,10-18

patients discontinued due to baseline resistance results6

*In a Phase 3 registrational trial of treatment-naïve patients (AMBER), only 1 patient receiving SYMTUZA® was found to have M184I/V. This patient also had a transmitted K103N mutation at screening. M184V was detected pretreatment by deep sequencing (Illumina MiSeq) as a minority variant (9.4%).1

AMBER (n=362); AMBER CONTROL (n=363); EMERALD (n=763); EMERALD CONTROL (n=266); DIAMOND (N=109); STUDY 130 (n=313); ARTEMIS (n=343); ODIN QD (n=294); ODIN BID (n=296); POWER 1 (n=65); POWER 2 (n=66); POWER 3 (n=336); METABOLIK (n=34); GRACE (n=429); DUET (n=599); DUET CONTROL (n=604); TITAN (n=298); PHASE 2 (n=103); PHASE 2 CONTROL (n=50)=5693.2,6,10-18

ALT=alanine aminotransferase; ARV=antiretroviral; AST=aspartate aminotransferase; BID=twice-daily; bPI=boosted protease inhibitor; CNS=central nervous system; DHHS=Department of Health and Human Services; DRV/c=darunavir/cobicistat; eGFR=estimated glomerular filtration rate; FTC=emtricitabine; HBV=hepatitis B virus; HIVTSQs=HIV Treatment Satisfaction Questionnaire status version; ITT=intent-to-treat; MDRD=Modification of Diet in Renal Disease; MSM=men who have sex with men; NPC=neurologic/psychiatric comorbidity; PrEP=pre-exposure prophylaxis; QD=once-daily; RAM=resistance-associated mutation; STR=single-tablet regimen; TDF=tenofovir disoproxil fumarate; ULN=upper limit normal; VF=virologic failure; VL=viral load.

 

References: 1. Eron JJ, Orkin C, Gallant J, et al; AMBER Study Group. A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS. 2018;32(11):1431-1442. 2. SYMTUZA® [package insert]. Titusville, NJ: Janssen Therapeutics, Division of Janssen Products, LP. 3. Orkin C, Eron JJ, Rockstroh J, et al; AMBER Study Group. Week 96 results of a phase 3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS. 2020;34(5):707-718. 4. Eron JJ, Orkin C, Cunningham D, et al; EMERALD Study Group. Week 96 efficacy and safety results of the phase 3, randomized EMERALD 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. Antiviral Res. 2019;170:104543. 5. Orkin C, Molina JM, Negredo E, et al; EMERALD Study Group. 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. Lancet HIV. 2018;5(1):e23-e34. 6. Huhn GD, Crofoot G, Ramgopal M, et al. Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in a rapid initiation model of care for HIV-1 infection: primary analysis of the DIAMOND study. Clin Infect Dis. Published online December 27, 2019. doi:10.1093/cid/ciz1213 7. Supplementary to: Huhn GD, Crofoot G, Ramgopal M, et al. Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in a rapid initiation model of care for HIV-1 infection: primary analysis of the DIAMOND study. Clin Infect Dis. Published online December 27, 2019. doi:10.1093/cid/ciz1213 8. Dunn K, Simonson RB, Luo D, et al. Use of D/C/F/TAF with neurologic/psychiatric comorbidities: AMBER subgroup analysis. Poster presented at: Conference on Retroviruses and Opportunistic Infections; March 8-11, 2020; Boston, MA. 9. Anderson D, Bolan R, DeJesus E, et al. Rapid initiation of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in patients with human immunodeficiency virus (HIV)–1 infection: age, race/ethnicity, and gender subgroup analyses from the DIAMOND Study. Poster presented at: 17th European AIDS Conference; November 6-9, 2019; Basel, Switzerland. 10. Tashima K, Crofoot G, Tomaka FL, et al. Cobicistat-boosted darunavir in HIV-1-infected adults: week 48 results of a phase IIIb, open-label single-arm trial. AIDS Res Ther. 2014;11:39. 11. 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(1):49-59. 12. 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(7):929-939. 13. Arastéh K, Yeni P, Pozniak A, et al. Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96. Antivir Ther. 2009;14(6):859-864. 14. Aberg JA, Tebas P, Overton ET, et al. Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treatment-naive, HIV type-1 infected subjects over 48 weeks. AIDS Res Hum Retroviruses. 2012;28(10):1184-1195. 15. Currier J, Averitt Bridge D, Hagins D, et al; GRACE (Gender, Race, and Clinical Experience) Study Group. Sex-based outcomes of darunavir-ritonavir therapy; a single-group trial. Ann Intern Med. 2010;153(6):349-357. 16. Katlama C, Clotet B, Mills A, et al. Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials. Antivir Ther. 2010;15(7):1045-1052. 17. Madruga JV, Berger D, McMurchie M, et al. TITAN Study Group. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet. 2007;370(9581):49-58. 18. Mills A, Crofoot G Jr, McDonald C, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate in the first protease inhibitor-based single-tablet regimen for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2015;69(4):439-445.