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

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

aUniversity of North Carolina School of Medicine, Chapel Hill, NC, USA

bQueen Mary University, London, UK

cPueblo Family Physicians, Phoenix, AZ, USA

dHIV Unit, Hospital 12 de Octubre, imas12, UCM, Madrid, Spain

eKing's College Hospital NHS Foundation Trust, London, United Kingdom;

fSaint-Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium

gJanssen Pharmaceutica NV, Beerse, Belgium

hJanssen Research & Development, Pennington, NJ, USA

*Corresponding author. Prof Joseph J. Eron, The University of North Carolina School of Medicine, Chapel Hill, NC 27599-7215. E-mail address:

jeron@med.unc.edu.

1

Supplementary table 1: Major protocol deviations and criteria leading to exclusion from the per-protocol analysis set

D/C/F/TAF

N = 763

Control

(bPI + F/TDF)

N = 378

Total

N = 1141

Patients with any major protocol deviation or criteria leading to

exclusion from the per-protocol set, n (%) 56 (7) 28 (7) 84 (7)

Entered but did not satisfy criteria 9 (1) 8 (2) 17 (1)

Received a disallowed concomitant treatment 3 (< 1) 1 (< 1) 4 (< 1)

Received wrong treatment or incorrect dose 3 (< 1) 3 (1) 6 (1)

Patient used disallowed medication 6 (1) 0 6 (1)

Other 17 (2) 8 (2) 25 (2)

Baseline VL value ≥ 50 copies/mL 16 (2) 7 (2) 23 (2)

Treatment adherence < 65%* 6 (1) 5 (1) 11 (1)

*Worst adherence from baseline to switch and from switch to week 96 was used for patients who started on bPI + F/TDF and switched to D/C/F/TAF at week 52.

Note: Patients may appear in more than 1 category.

bPI + F/TDF, boosted protease inhibitor plus emtricitabine/tenofovir-disoproxil-fumarate once daily; D/C/F/TAF, darunavir/cobicistat/emtricitabine/tenofovir

alafenamide once daily.

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Supplementary table 2: Baseline demographics and disease characteristics

Demographics

D/C/F/TAF

N = 763

Control

(bPI + F/TDF)

N = 378

Total

N = 1141

Median (range) age, years 46 (19–75) 45 (20–78) 46 (19–78)

> 65

> 50

25 (3)

256 (34)

8 (2)

126 (33)

33 (3)

382 (33)

Sex

Female 140 (18) 65 (17) 205 (18)

Male 623 (82) 313 (83) 936 (82)

Race

White 573 (75) 282 (75) 855 (75)

Black/African American 155 (20) 82 (22) 237 (21)

Asian/other races 35 (5) 14 (4) 49 (4)

Region

North America 358 (47) 202 (53) 560 (49)

3

Europe 405 (53) 176 (47) 581 (51)

Baseline characteristics

Median (IQR) CD4+ cell count, cells per μL 630 (468–806) 624 (466–795) 628 (468–802)

WHO clinical stage 4 HIV-1 infection 79 (10) 36 (10) 115 (10)

Median (IQR) eGFRcr, mL/min (Cockcroft-Gault) 104.2 (86.9–122.5) 103.3 (86.3–122.4)* 104.2 (86.8–122.4)

Median (IQR) time since diagnosis, years 9.3 (4.2–18.6) 8.9 (4.3–17.5) 9.3 (4.2–18.1)

Median (IQR) time since first ART, years 6.23 (3.46–13.51) 5.75 (3.45–12.85)† 6.05 (3.45–13.21)‡

Previous use of ≥ 5 antiretrovirals

(including screening antiretrovirals)§ 447 (59) 217 (57) 664 (58)

≥ 2 PIs (including screening PIs) 318 (42) 154 (41) 472 (41)

≥ 3 N(t)RTIs (including screening N(t)RTIs) 328 (43) 146 (39) 474 (42)

≥ 1 NNRTI 225 (29) 115 (30) 340 (30)

≥ 1 integrase inhibitor 39 (5) 24 (6) 63 (6)

Previous antiretroviral VF 116 (15) 53 (14) 169 (15)

PI 51 (7) 29 (8) 80 (7)

N(t)RTI 90 (12) 40 (11) 130 (11)

4

NNRTI 50 (7) 24 (6) 74 (6)

Integrase inhibitor 7 (1) 3 (1) 10 (1)

Boosted PI at screening

Darunavir 537 (70) 266 (70) 803 (70)

Darunavir with ritonavir 439 (58) 202 (53) 641 (56)

Darunavir with cobicistat 98 (13) 64 (17) 162 (14)

Atazanavir 167 (22) 82 (22) 249 (22)

Atazanavir with ritonavir 161 (21) 81 (21) 242 (21)

Atazanavir with cobicistat 6 (1) 1 (<1) 7 (1)

Lopinavir/ritonavir 59 (8) 30 (8) 89 (8)

Data are n (%) unless otherwise stated.

*N = 761; †N = 377; ‡N = 1140; §PI booster is counted as a separate antiretroviral.

ART, antiretroviral therapy; bPI + F/TDF, boosted protease inhibitor plus emtricitabine/tenofovir-disoproxil-fumarate once daily; D/C/F/TAF,

darunavir/cobicistat/emtricitabine/tenofovir alafenamide once daily; eGFRcr, eGFR based on serum creatinine; NNRTI, non-nucleoside analog reverse

transcriptase inhibitor; N(t)RTI, nucleoside or nucleotide analog reverse transcriptase inhibitor; PI, protease inhibitor; WHO, World Health Organization.

5

Supplementary table 3: Protocol-defined virologic rebound (≥ 50 copies/mL) cumulative through Week 96 and virologic outcomes (FDA-snapshot

analysis) at Week 96 (per-protocol analysis)

PDVR Cumulative Through

Week 96

Virologic Outcomes (FDA-Snapshot) at Week 96

VL <50 copies/mL VL ≥50 copies/mL

Treatment Arm N n (%) (95% CI)* n (%) (95% CI)* n (%) (95% CI)*

D/C/F/TAF 707 16 (2.3) (1.3 to 3.6) 652 (92.2) (90.0 to 94.1) 5 (0.7) (0.2 to 1.6)

Late switch to D/C/F/TAF† 331 7 (2.1) (0.9 to 4.3) 312 (94.3) (91.2 to 96.5) 6 (1.8) (0.7 to 3.9)

*Two-sided Exact Clopper-Pearson 95% CI.

†Late switch to D/C/F/TAF comprises 44 weeks of D/C/F/TAF exposure (i.e., from the switch to D/C/F/TAF at week 52).

D/C/F/TAF, darunavir/cobicistat/emtricitabine/tenofovir alafenamide once daily.

6

Supplementary table 4: Virologic outcomes according to the FDA-snapshot analysis at Week 96

Virologic Outcomes*, n (%) D/C/F/TAF Late Switch to D/C/F/TAF†

N = 763 N = 352

50 copies/mL n (%) 95% CI‡ n (%) 95% CI‡

Virologic response

VL < 50 copies/mL 692 (90.7) (88.4 to 92.7) 330 (93.8) (90.7 to 96.0)

VL ≥ 50 copies/mL 9 (1.2) (0.5 to 2.2) 6 (1.7) (0.6 to 3.7)

Last VL in week 96 window ≥ 50 copies/mL 5 (0.7) 6 (1.7)

Discontinued for efficacy reasons 0 0

Discontinued due to other reasons than efficacy,

adverse events or death and last available VL ≥ 50

copies/mL

4 (0.5) 0

No VL data in week 96 window 62 (8.1) 16 (4.5)

7

Discontinued due to AE/death 18 (2.4) 6 (1.7)

Discontinued due to other reasons and last available

VL < 50 copies/mL (or missing)38 (5.0) 7 (2.0)

Missing data during window but on study drug 6 (0.8) 3 (0.9)

200 copies/mL N = 763 N = 352

Virologic response

VL < 200 copies/mL 696 (91.2) (89.0 to 93.1) 336 (95.5) (92.7 to 97.4)

VL ≥ 200 copies/mL 2 (0.3) (0.0 to 0.9) 0

Last VL in week 96 window ≥50 copies/mL 1 (0.1) 0

Discontinued for efficacy reasons 0 0

Discontinued due to other reasons than efficacy,

adverse events or death and last available VL ≥ 50

copies/mL

1 (0.1) 0

No VL data in week 96 window 65 (8.5) 16 (4.5)

Discontinued due to AE/death 18 (2.4) 6 (1.7)

8

Discontinued due to other reasons and last available

VL < 50 copies/mL (or missing)41 (5.4) 7 (2.0)

Missing data during window but on study drug 6 (0.8) 3 (0.9)

*Last available VL value in the week 96 time-point window (week 90‒102) was used to determine response.

†Comprising 44 weeks of D/C/F/TAF exposure (i.e. from the switch to D/C/F/TAF at week 52).

‡Two-sided Exact Clopper-Pearson 95% CI.

AE, adverse event; CI, confidence interval; D/C/F/TAF, darunavir/cobicistat/emtricitabine/tenofovir alafenamide once daily; VL, viral load.

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Supplementary table 5: Protocol-defined virologic rebound (≥ 50 copies/mL) cumulative through week 96 and virologic outcomes (FDA-snapshot

analysis) at Week 96 by subgroup

PDVR Cumulative Through

Week 96

Virologic Outcomes (FDA-Snapshot) at Week 96

VL < 50 copies/mL VL ≥ 50 copies/mL

Subgroup Treatment Arm N n (%) (95% CI)* n (%) (95% CI)* n (%) (95% CI)*

Sex

Female

D/C/F/TAF 140 4 (2.9) (0.8 to 7.2) 120 (85.7) (78.8 to 91.1) 2 (1.4) (0.2 to 5.1)

Late switch to D/C/F/TAF† 60 0 - 53 (88.3) (77.4 to 95.2) 0

Male

D/C/F/TAF 623 20 (3.2) (2.0 to 4.9) 572 (91.8) (89.4 to 93.8) 7 (1.1) (0.5 to 2.3)

Late switch to D/C/F/TAF† 292 8 (2.7) (1.2 to 5.3) 277 (94.9) (91.7 to 97.1) 6 (2.1) (0.8 to 4.4)

Age

≤ 50 years

D/C/F/TAF 507 18 (3.6) (2.1 to 5.6) 460 (90.7) (87.9 to 93.1) 9 (1.8) (0.8 to 3.3)

Late switch to D/C/F/TAF† 235 5 (2.1) (0.7 to 4.9) 221 (94.0) (90.2 to 96.7) 4 (1.7) (0.5 to 4.3)

>50 years

10

D/C/F/TAF 256 6 (2.3) (0.9 to 5.0) 232 (90.6) (86.4 to 93.9) 0

Late switch to D/C/F/TAF† 117 3 (2.6) (0.5 to 7.3) 109 (93.2) (87.0 to 97.0) 2 (1.7) (0.2 to 6.0)

Race

White

D/C/F/TAF 573 17 (3.0) (1.7 to 4.7) 527 (92.0) (89.4 to 94.1) 6 (1.0) (0.4 to 2.3)

Late switch to D/C/F/TAF† 260 5 (1.9) (0.6 to 4.4) 248 (95.4) (92.1 to 97.6) 4 (1.5) (0.4 to 3.9)

Black or African American

D/C/F/TAF 155 7 (4.5) (1.8 to 9.1) 133 (85.8) (79.3 to 90.9) 3 (1.9) (0.4 to 5.6)

Late switch to D/C/F/TAF† 78 3 (3.8) (0.8 to 10.8) 68 (87.2) (77.7 to 93.7) 2 (2.6) (0.3 to 9.0)

Asian

D/C/F/TAF 17 0 - 16 (94.1) (71.3 to 99.9) 0

Late switch to D/C/F/TAF† 9 0 - 9 (100.0) (66.4 to 100.0) 0

American Indian or Alaska Native

D/C/F/TAF 5 0 - 4 (80.0) (28.4 to 99.5) 0

Late switch to D/C/F/TAF† 2 0 - 2 (100.0) (15.8 to 100.0) 0

Native Hawaiian or Other Pacific Islander

D/C/F/TAF 2 0 - 2 (100.0) (15.8 to 100.0) 0

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Other

D/C/F/TAF 5 0 - 4 (80.0) (28.4 to 99.5) 0

Late switch to D/C/F/TAF† 1 0 - 1 (100.0) (2.5 to 100.0) 0

non-Black or African American

D/C/F/TAF 597 17 (2.8) (1.7 to 4.5) 549 (92.0) (89.5 to 94.0) 6 (1.0) (0.4 to 2.2)

Late switch to D/C/F/TAF† 271 5 (1.8) (0.6 to 4.3) 259 (95.6) (92.4 to 97.7) 4 (1.5) (0.4 to 3.7)

Number of previous antiretrovirals used

3

D/C/F/TAFb 1 0 - 1 (100.0) (2.5 to 100.0) 0

4

D/C/F/TAF 316 9 (2.8) (1.3 to 5.3) 296 (93.7) (90.4 to 96.1) 3 (0.9) (0.2 to 2.7)

Late switch to D/C/F/TAF† 154 4 (2.6) (0.7 to 6.5) 143 (92.9) (87.6 to 96.4) 4 (2.6) (0.7 to 6.5)

5

D/C/F/TAF 98 4 (4.1) (1.1 to 10.1) 88 (89.8) (82.0 to 95.0) 1 (1.0) (0.0 to 5.6)

Late switch to D/C/F/TAF† 50 2 (4.0) (0.5 to 13.7) 46 (92.0) (80.8 to 97.8) 1 (2.0) (0.1 to 10.6)

6

D/C/F/TAF 69 5 (7.2) (2.4 to 16.1) 64 (92.8) (83.9 to 97.6) 1 (1.4) (0.0 to 7.8)

12

Late switch to D/C/F/TAF† 30 0 - 28 (93.3) (77.9 to 99.2) 0

7

D/C/F/TAF 69 0 - 61 (88.4) (78.4 to 94.9) 0

Late switch to D/C/F/TAF† 25 1 (4.0) (0.1 to 20.4) 21 (84.0) (63.9 to 95.5) 1 (4.0) (0.1 to 20.4)

>7

D/C/F/TAF 211 6 (2.8) (1.1 to 6.1) 183 (86.7) (81.4 to 91.0) 4 (1.9) (0.5 to 4.8)

Late switch to D/C/F/TAF† 92 1 (1.1) (0.0 to 5.9) 91 (98.9) (94.1 to 100.0) 0

Previous antiretroviral VF

0

D/C/F/TAF 647 19 (2.9) (1.8 to 4.5) 591 (91.3) (88.9 to 93.4) 5 (0.8) (0.3 to 1.8)

Late switch to D/C/F/TAF† 304 7 (2.3) (0.9 to 4.7) 284 (93.4) (90.0 to 95.9) 6 (2.0) (0.7 to 4.2)

≥1

D/C/F/TAF 116 5 (4.3) (1.4 to 9.8) 101 (87.1) (79.6 to 92.6) 4 (3.4) (0.9 to 8.6)

Late switch to D/C/F/TAF† 48 1 (2.1) (0.1 to 11.1) 46 (95.8) (85.7 to 99.5) 0

*Two-sided Exact Clopper-Pearson 95% CI.

†Late switch to D/C/F/TAF comprises 44 weeks of D/C/F/TAF exposure (i.e., from the switch to D/C/F/TAF at week 52).

D/C/F/TAF, darunavir/cobicistat/emtricitabine/tenofovir alafenamide once daily.

Supplementary table 6: Categorical distribution of percentage change from reference at Weeks 48 and 96 in hip, spine, and femoral neck BMD

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and Change in BMD T-score in the bone investigation substudy.

Hip Lumbar Spine Femoral Neck

D/C/F/TAF Arm Late Switch Arm D/C/F/TAF Arm Late Switch Arm D/C/F/TAF Arm Late Switch Arm

D/C/F/TAF

(week 48)

N = 186

D/C/F/TAF

(week 96†)

N = 164

bPI+F/TDF

(week 48)

N = 95

D/C/F/TAF*

(week 96†)

N = 96

D/C/F/TAF

(week 48)

N = 189

D/C/F/TAF

(week 96†)

N = 173

bPI+F/TDF

(week 48)

N = 99

D/C/F/TAF*

(week 96†)

N = 99

D/C/F/TAF

(week 48)

N = 186

D/C/F/TAF

(week 96†)

N = 164

bPI+F/TDF

(week 48)

N = 95

D/C/F/TAF*

(week 96†)

N = 96

Patients with ≥ 3%/5%/7% change from reference in BMD, n (%)

Increase

by ≥ 3% 39 (21) 47 (29) 4 (4) 23 (24) 59 (31) 64 (37) 9 (9) 43 (43) 45 (24) 47 (29) 11 (12) 28 (29)

Increase

by ≥ 5% 11 (6) 18 (11) 1 (1) 10 (10) 29 (15) 32 (19) 2 (2) 17 (17) 15 (8) 23 (14) 4 (4) 12 (13)

Increase

by ≥ 7% 5 (3) 5 (3) 0 3 (3) 6 (3) 13 (8) 2 (2) 8 (8) 7 (4) 8 (5) 1 (1) 5 (5)

Decrease

by ≥ 3% 4 (2) 5 (3) 8 (8) 5 (5) 15 (8) 16 (9) 20 (20) 2 (2) 19 (10) 14 (9) 17 (18) 9 (9)

Decrease 0 0 2 (2) 2 (2) 3 (2) 6 (4) 9 (9) 1 (1) 5 (3) 3 (2) 8 (8) 5 (5)

14

by ≥ 5%

Decrease

by ≥ 7% 0 0 0 2 (2) 2 (1) 2 (1) 3 (3) 1 (1) 0 0 2 (2) 5 (5)

Patients with improved or worsening BMD T-score vs. reference, n (%)

Improved

T-scorea

6/188

(3)c

9/166

(5)

1/97

(1)c

7/96

(7)

16/192

(8)c

22/174

(13)

4/101

(4)c

16/99

(16)

10/188

(5)c

9/166

(5)

3/97

(3)c

7/96

(7)

Worsening

T-scoreb

0/188

(0)c

2/166

(1)

2/97

(2)c

3/96

(3)

7/192

(4)c

6/174

(3)

4/101

(4)c

1/99

(1)

5/188

(3)c

5/166

(3)

5/97

(5)c

1/96

(1)

*Comprising ~44 weeks of D/C/F/TAF exposure (i.e. from the switch to D/C/F/TAF at week 52).

†For the change at week 96, reference for D/C/F/TAF arm is baseline and for late switch (D/C/F/TAF) is the last value before the switch.

aOsteopenia to normal, or from osteoporosis to normal or osteopenia.

bNormal to osteopenia or normal or osteopenia to osteoporosis.

cResults from the week 48 analysis.

Normal 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.

BMD, bone mineral density; bPI+F/TDF, boosted protease inhibitor plus emtricitabine/tenofovir disoproxil fumarate once daily; D/C/F/TAF,

darunavir/cobicistat/emtricitabine/tenofovir alafenamide once daily.

15

Supplementary figure 1: Median fasting lipid levels at baseline, week 48 and week 96.

LDL-C, low-density lipoprotein-cholesterol; TC, total cholesterol; HDL-C, high-density lipoprotein-cholesterol.

*P < 0.001 for within treatment arm changes at week 96 from reference (assessed by Wilcoxon signed-rank test).

†Reference for the D/C/F/TAF arm is baseline and for the late switch (D/C/F/TAF) arm is the last value before the switch.

16

17

Supplementary figure 2: Median absolute change from reference at weeks 48 and 96 in A) renal biomarkers and B) bone biomarkers in the bone

investigation substudy.

*Comprising ~44 weeks of D/C/F/TAF exposure (i.e., from the switch to D/C/F/TAF at week 52).

†All P < 0.001 for within treatment arm changes at week 96 from reference (assessed by Wilcoxon signed-rank test).

‡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.

18