Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Orkin C, DeJesus E, Sax PE, et al. Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials. Lancet HIV 2020; 7: e389–400.

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Appendices

We thank the following GS-US-380-1489 and GS-US-380-1490 Investigators and their staff:

Abreu Edel Akil Bisher Albrecht Helmut Andany Nisha Angel Jonathan Antela Lopez Antonio Antinori Andrea Arastéh Keikawus Arribas Jose Asmuth David Bartczak Jennifer Baumgarten Axel Belkhir Leila Bell David Bellos Nicholaos Bennani Yussef Benson Paul Berenguer Juan Berger Daniel Berhe Mezgebe Bernard Louis Bird Elspeth Bloch Mark Bordon Jose Brar Indira Brinson Cynthia Brunetta Jason Burack Jeffrey Campo Rafael Chaponda Mas Charest Louise Chasanov William Cindrich Richard Clarke Amanda Clotet Bonaventura Colson Amy Cook Paul Cotte Laurent

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Coulston Daniel Cox Joseph Creticos Catherine Crofoot Gordon Cruickshank Frederick Cruickshank Frederick Cunningham Douglas Daar Eric de Wet Joseph Degen Olaf DeJesus Edwin Dietz Craig Dragovic Bojana Dronda Fernando Edelstein Howard Eron Joseph Esser Stefan Estrada Perez Vicente Fätkenheuer Gerd Fichtenbaum Carl Finlayson Robert Flamm Jason Florence Eric Fox Julie Gallant Joel Gathe Joseph Girard Pierre-Marie Goldstein Deborah Gorgos Linda Greiger-Zanlungo Paola Grossberg Robert Gupta Samir Hagins Debbie Hamzah Lisa Hardy W. David Hare C. Bradley Hassler Shawn Hay Phillip Henn Sarah Henry Keith Hileman Corrilynn

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Hite Amy Hsiao Chiu-Bin Hsu Ricky Huhn Gregory Iandiorio Michelle Jäger Hans Jain Mamta Jayaweera Dushyantha Johnson Margaret Johnson Marc Jordan Wilbert Kasper Ken Kinder Clifford Klein Daniel Koenig Ellen Lamarca Anthony Lazzarin Adriano LeBlanc Roger Lebouche Bertrand Leen Clifford Lehmann Clara Lucasti Christopher Lutz Thomas Maggiolo Franco Mallolas Masferrer Josep Marquez Solero, Manuel Martorell Claudia Mauss Stefan Mayer Cynthia McDonald Cheryl McGowan Joseph McKellar Mehri McLeod Gavin McMahon James Meybeck Agnes Mills Anthony Miralles Celia Mogyoros Miguel Molina Jean-Michel Moore Richard Morales-Ramirez Javier

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Moreno Santiago Mounzer Karem Nahass Ronald Newman Cheryl Nolan Rathel Oguchi Godson Orkin Chloe Osiyemi Olayemi Pakianathan Mark Palacios Rosario Palmieri Philip Para Michael Park Connie Parks David Parsons Christopher Petroll Andrew Peyrani Paula Pierone Gerald Podzamczer Daniel Polk Christopher Portilla Sogorb Joaquín Portilla Sogorb Joaquin Post Frank Pozniak Anton Prelutsky David Pugliese Pascal Pulido Federico Rachlis Anita Raffi François Ramgopal Moti Rashbaum Bruce Redfield Robert Reynes Pr Jacques Rhame Frank Richmond Gary Rivero Roman Antonio Roberts Afsoon Rockstroh Jürgen Ross Jonathan Roth Norman Ruane Peter

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Rubio Rafael Saag Michael Salazar Laura Santana-Bagur Jorge L Santiago Lizette Sax Paul Scarsella Anthony Schembri Gabriel Schmidt Martina Schrader Shannon Scott Mia Scribner Anita Segal-Maurer Sorana Shalit Peter Shamblaw David Shon Alyssa Shor Asaf Sims James Sinclair Gary Slim Jihad Sokol-Anderson Marcia Stein David Stellbrink, Hans-Jürgen Stephan Christoph Stephens Jeffrey Szabo Jason Taylor Stephen Tebas-Medrano Pablo Thompson Melanie Thormann Peynado

Monica

Towner William Ustianowski Andrew Van Dam Cornelius Vandekerckhove Linos Vandercam Bernard Vanig Thanes Voskuhl Gene Wade Barbara Waldman Sarah Walker Durane

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Walmsley Sharon Ward Douglas Waters Laura Wheeler David Whitehead Mitchell Wiberg Kjell Wilkin Aimee Wills Todd Winston Alan Wohl David Wohlfeiler MIchael Woolley Ian Workowski Kimberly Wurapa Anson Yazdanpanah Yazdan Yin Michael Young Benjamin Zorrilla Carmen Zurawski Christine

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Appendix Table 1. Virologic outcomes at week 144 in participants with cumulative study drug adherence <95%(Study 1489)

Bictegravir, emtricitabine, and tenofovir alafenamide

(n=102)

Dolutegravir, abacavir, and

lamivudine (n=118)

Bictegravir, emtricitabine. and tenofovir alafenamide vs Dolutegravir, abacavir, and

lamivudine Difference in Percentages

(CI)† HIV-1 RNA <50 copies per mL 66 (64.7%) 92 (78.0%) -13.0% (-25.1% to -1.0%) HIV-1 RNA ≥50 copies per mL 1 (1.0%) 7 (5.9%)

HIV-1 RNA ≥50 copies per mL 1 (1.0%) 2 (1.7%) Discontinued Due to Lack of Efficacy 0 0 Discontinued Due to Other Reasons* and Last Available HIV-1 RNA ≥50 copies per mL

0 5 (4.2%)

No Virologic Data 35 (34.3%) 19 (16.1%) Discontinued Due to AE/Death¥ 2 (2.0%) 3 (2.5%) Discontinued Due to Other Reasons* and Last Available HIV-1 RNA <50 copies per mL

31 (30.4%) 15 (12.7%)

Missing Data but on Study Drug 2 (2.0%) 1 (0.8%) Data are n (%). The Week 144 window is between Days 967 and 1050 (inclusive). *Other reasons include subjects who discontinued study drug due to investigator’s discretion, participant decision, lost to follow-up,

noncompliance with study drug, protocol violation, pregnancy. † The difference in percentages of subjects with HIV-1 RNA < 50 copies/mL between treatment groups and its 95% CI were

calculated based on the MH proportions adjusted by baseline HIV-1 RNA stratum and region stratum.

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Appendix Table 2. Study drug-related adverse events in ≥2% in either group at week 144 (Study 1489)

Bictegravir, emtricitabine, and tenofovir alafenamide

(n=314)

Dolutegravir, abacavir, and lamivudine

(n=315)

Any study drug-related adverse event 94 (30%) 132 (42%)

Study drug-related adverse event in ≥1 participant

Nausea 18 (6%) 56 (18%)

Diarrhea 19 (6%) 13 (4%)

Headache 16 (5%) 16 (5%)

Fatigue 9 (3%) 11 (4%)

Abnormal dreams 8 (3%) 8 (3%)

Dizziness 7 (2%) 9 (3%)

Insomnia 6 (2%) 9 (3%)

Vomiting 3 (1%) 9 (3%)

Data are n (%).

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Appendix Table 3. Study drug-related adverse events in ≥2% in either group at week 144 (Study 1490)

Bictegravir, emtricitabine, and tenofovir alafenamide

(n=320)

Dolutegravir plus emtricitabine, and

tenofovir alafenamide (n=325)

Any study drug-related adverse event 71 (22%) 95 (29%)

Study drug-related adverse event in ≥1 participant

Nausea 10 (3%) 17 (5%)

Headache 14 (4%) 10 (3%)

Diarrhoea 10 (3%) 10 (3%)

Fatigue 7 (2%) 7 (2%)

Dizziness 7 (2%) 3 (1%)

Flatulence 3 (1%) 7 (2%)

Abdominal distension 3 (1%) 5 (2%)

Insomnia 7 (2%) 1 (<1%)

Data are n (%).

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Appendix Table 4. Grade 3 or 4 laboratory abnormalities in ≥2% of participants in either group through week 144 (Study 1489)

Bictegravir, emtricitabine, and

tenofovir alafenamide (n=314)

Dolutegravir, abacavir, and lamivudine

(n=315)

Any Grade 3 or 4 Treatment-Emergent Toxicity Grade

83/314 (26%) 80/315 (25%)

Neutrophils (Decreased) 10/314 (3%) 13/315 (4%)

ALT (Increased) 7/314 (2%) 6/315 (2%)

Amylase (Increased) 8/314 (3%) 14/315 (4%)

AST (Increased) 15/314 (5%) 10/315 (3%)

Creatine Kinase (Increased) 25/314 (8%) 24/315 (8%)

GGT (Increased) 5/314 (2%) 5/315 (2%)

LDL (Fasting, Increased) 14/308 (5%) 15/310 (5%)

Urine Glucose (Glycosuria) 4/314 (1%) 5/315 (2%)

Urine RBC (Hematuria, Quantitative) 2/314 (1%) 8/315 (3%)

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Appendix Table 5. Grade 3 or 4 laboratory abnormalities in ≥2% of participants in either group (Study 1490)

Bictegravir, emtricitabine, and

tenofovir alafenamide (n=320)

Dolutegravir plus emtricitabine, and

tenofovir alafenamide (n=325)

Any Grade 3 or 4 Treatment-Emergent Toxicity Grade

77/314 (25%) 74/325 (23%)

Neutrophils (Decreased) 9/313 (3%) 5/325 (2%)

Amylase (Increased) 10/313 (3%) 12/325 (4%)

ALT (Increased) 10/313 (3%) 4/325 (1%)

AST (increased) 7/313 (2%) 9/325 (3%)

Creatine Kinase (Increased) 20/313 (6%) 13/325 (4%)

Serum Glucose (Fasting, increased) 5/312 (2%) 13/325 (4%)

Serum Glucose (Nonfasting, increased) 2/188 (1 %) 3/184 (2%)

Total Cholesterol (Fasting, increased) 5/305 (2%) 3/317 (0.9%)

LDL (Fasting, Increased) 13/305 (4%) 19/317 (6%)

Urine Glucose (Glycosuria) 4/313 (1%) 13/325 (4%)

Urine RBC (Hematuria, Quantitative or Dipstick) 4/313 (1%) 7/325 (2%) ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDL, low-density lipoprotein The denominator for percentage is the number of subjects with at least 1 postbaseline value for the test under evaluation.

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Appendix Table 6. Changes in quantitative measures of renal function and proteinuria from baseline at week 144

Study 1489

P-value

Study 1490

P-value

Bictegravir, emtricitabine, and

tenofovir alafenamide (n=314)

Dolutegravir, abacavir,

and lamivudine (n=315)

Bictegravir, emtricitabine, and

tenofovir alafenamide (n=320)

Dolutegravir plus emtricitabine, and tenofovir

alafenamide (n=325)

n Median (Q1, Q3) n Median (Q1, Q3) n Median (Q1, Q3) n Median (Q1, Q3)

Serum creatinine (mg per dL)

Baseline 314 0.90 (0.80, 1.00) 315 0.91 (0.81, 0.99) 0.92 320 0.91 (0.80, 1.02) 325 0.89 (0.79, 1.00) 0.10

Change at week 144 258 0.10 (0.04, 0.19) 266 0.11 (0.04, 0.19) 0.60 263 0.11 (0.03, 0.19) 279 0.12 (0.06, 0.21) 0.17

eGFR*(mL per min)

Baseline 314 125.9 (107.7, 146.3) 315 123.0 (107.0, 144.3) 0.76 320 120.4 (100.8, 141.8) 325 120.6 (102.8, 145.1) 0.27

Change at week 144 258 -9.6 (-20.9, 0.0) 266 -11.7 (-22.7, -0.6) 0.34 263 −9.0 (−18.7, −0.3) 279 −11.0 (−22.0, 0.1) 0.19

Urine albumin to creatinine ratio (mg per g)

Baseline 309 5.5 (3.7, 9.2) 312 5.4 (3.7, 9.1) 0.72 – – – – – Percentage change at week 144 254 2.6 (-33.4, 62.9) 260 -1.6 (-29.6, 61.8) 0.94 – – – – –

Urine β2-microglobulin to creatinine ratio (µg per g)

Baseline 307 108.1 (71.7, 184.4) 311 109.8 (77.6, 191.8) 0.92 – – – – – Percentage change at week 144 250 -26.4 (-59.5, 18.7) 258 -34.2 (-58.8, 0.9) 0.41 – – – – –

Urine retinol binding protein to creatinine ratio (µg per g)

Baseline 308 81.0 (58.3, 122.4) 312 83.7 (59.8, 120.4) 0.55 – – – – – Percentage change at week 144 252 19.6 (−13.4, 60.3) 260 15.4 (−20.5, 66.9) 0.83 – – – – –

*As calculated by the Cockcroft-Gault formula P-values were from the 2-sided Wilcoxon rank sum test to compare the 2 treatment groups.

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Appendix Table 7. Changes from baseline in fasting metabolic laboratory parameters and body weight at week 144

Metabolic Assessment

Study 1489

p-value

Study 1490

p-value

Bictegravir, emtricitabine, and

tenofovir alafenamide (n=314)

Dolutegravir, abacavir,

and lamivudine (n=315)

Bictegravir, emtricitabine, and

tenofovir alafenamide (n=320)

Dolutegravir plus emtricitabine, and

tenofovir alafenamide (n=325)

n Median (Q1, Q3) n Median (Q1, Q3) n Median (Q1, Q3) n Median (Q1, Q3)

Total cholesterol (mg/dL)

Baseline 305 159 (133, 181) 305 162 (138, 186) 0.23 314 156 (136, 182) 321 161 (138, 186) 0.30

Change at week 144 247 14 (−5, 32) 256 10 (−10, 27) 0.034 256 12 (−9, 34) 274 12 (−12, 33) 0.88

Direct LDL (mg/dL)

Baseline 305 101 (83, 123) 305 101 (84, 126) 0.46 314 98 (81, 120) 321 99 (82, 124) 0.46

Change at week 144 247 21 (5, 41) 256 14 (−2, 32) 0.004 256 19 (0, 39) 274 19 (1, 38) 0.68

Triglycerides (mg/dL)

Baseline 305 93 (67, 132) 305 96 (66,138) 0.74 314 97 (72, 134) 321 95 (70, 131) 0.40

Change at week 144 247 6 (−19, 39) 255 5 (−20, 31) 0.23 256 2 (−27, 33) 274 2 (−25, 31) 0.97

HDL (mg/dL)

Baseline 305 42 (34, 51) 305 42 (35, 51) 0.62 314 43 (35, 52) 321 43 (35, 52) 0.97

Change at week 144 247 5 (−2, 10) 256 6 (0, 13) 0.096 256 3 (−3, 10) 274 5 (−1, 12) 0.17

Total cholesterol to HDL ratio

Baseline 305 3.7 (3.0, 4.7) 305 3.7 (3.0, 4.6) 0.93 314 3.7 (3.0, 4.5) 321 3.7 (3.1, 4.5) 0.85

Change at week 144 247 −0.1 (−0.5, 0.5) 256 −0.3 (−0.8, 0.3) 0.007 256 0.0 (−0.6, 0.4) 274 −0.1 (−0.6, 0.4) 0.24

Body weight (kg)

Baseline 314 77.2 (68.0, 88.0) 315 78.0 (68.2, 89.8) – 320 75.8 (67.8, 87.3) 325 76.2 (67.1, 89.3) –

Change at week 144 260 4.1 (0.3, 8.7) 267 3.5 (0.0, 7.7) – 263 4.4 (1.0, 9.0) 279 5.0 (0.5, 9.7) –

eGFR, estimated glomerular filtration rate;HDL, high density lipoprotein; LDL, low density lipoprotein; Q, quartile Only lipid and glucose measurements under fasting status were summarized. P-values were from the 2-sided Wilcoxon rank sum test to compare the 2 treatment groups.

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Appendix Figure 1. Forest Plot of Treatment Difference in HIV-1 RNA <50 copies/mL at Week 144 (Snapshot Algorithm) by Subgroup (Study 1489)

The Week 144 window is between Days 967 and 1050 (inclusive). proportions adjusted by baseline HIV-1 RNA (<= 100,000 vs. > 100,000 copies/mL) and region The difference in percentages of subjects with HIV-1 RNA < 50 copies/mL between treatment groups and its 95% CI were calculated based on the MH stratum (US vs. Ex-US) (if not the subgroup factor). Study drug adherence subgroup analyses are based on the adherence up to Week 144 visit for active study drug. Relative to the vertical line at 0, differences on the right favor the B/F/TAF group and differences on the left favor the ABC/DTG/3TC group. * = Proportion difference and 95% CI from normal approximation without stratification as they were not calculable by stratum-adjusted MH method

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Appendix Figure 2. Forest Plot of Treatment Difference in HIV-1 RNA <50 copies/mL at Week 144 (Snapshot Algorithm) by Subgroup (Study 1490)

The Week 144 window is between Days 967 and 1050 (inclusive). proportions adjusted by baseline HIV-1 RNA (<= 100,000 vs. > 100,000 copies/mL) and region The difference in percentages of subjects with HIV-1 RNA < 50 copies/mL between treatment groups and its 95% CI were calculated based on the MH stratum (US vs. Ex-US) (if not the subgroup factor). Study drug adherence subgroup analyses are based on the adherence up to Week 144 visit for active study drug. Relative to the vertical line at 0, differences on the right favor the B/F/TAF group and differences on the left favor the DTG+F/TAF group. * = Proportion difference and 95% CI from normal approximation without stratification as they were not calculable by stratum-adjusted MH method

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Appendix Figure 3. Prevalence and incidence of nausea through 144 weeks in Study 1489

B/F/TAF, bictegravir, emtricitabine, and tenofovir alafenamide; DTG/ABC/3TC, dolutegravir, abacavir, lamivudine

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Appendix Figure 4. Weight change through week 144