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IAS 2019, Mexico City

Switching to a Single-tablet Regimen of Bictegravir , Emtricitabine, and Tenofovir Alafenamide (B/F/TAF) from Dolutegravir plus Either F/TAF or F/TDF.

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IAS 2019, Mexico City

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  1. Switching to a Single-tablet Regimen of Bictegravir, Emtricitabine, and Tenofovir Alafenamide (B/F/TAF) from Dolutegravir plus Either F/TAF or F/TDF Paul E. Sax1, Jürgen Rockstroh2, Anne F. Luetkemeyer3, Yazdan Yasdanpanah4, Douglas Ward5, Benoit Trottier6, Armin Rieger7, Hui Liu8, Rima Acosta8, Sean E. Collins8, Diana Brainard8, Hal Martin8 on behalf of the 380-4030 Investigators 1Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA; 2University Hospital Bonn, Bonn, Germany; 3University of California San Francisco, California, USA; 4Hôpital Bichat Claude Bernard, Paris, France; 5Dupont Circle Physicians Group, Washington DC, USA; 6Clinique de MedecineUrbaine du Quartier Latin, Montreal, Quebec, Canada; 7University of Vienna Medical School, Vienna, Austria; 8Gilead Sciences, Inc., Foster City, CA, US IAS 2019, Mexico City

  2. Disclosures and Acknowledgments Dr. Sax has research grants paid to his institution from Gilead and ViiV-GlaxoSmithKline, and consulting fees from Gilead, Janssen, Merck, and ViiV-GlaxoSmithKline. This study was funded by Gilead Sciences, Inc. We thank the participants and their families.

  3. Introduction • HIV treatment guidelines increasingly focus on INSTI-based regimens due to their favorable efficacy, safety and tolerability • Bictegravir, an INSTI with a high resistance barrier, is co-formulated with emtricitabine and tenofovir alafenamide (B/F/TAF) to provide a one-pill, once-daily regimen • B/F/TAF and DTG + F/TAF are both guidelines-recommended initial regimens1-3 and can be used in HIV and HBV coinfection • Unrecognized resistance mutations may be present even among virologicallysuppressed patients4 • Switching to B/F/TAF in virologically suppressed patients with a history of treatment failure and/or known or suspected pre-existing NRTI drug resistance has not been prospectively investigated DTG, dolutegravir; HBV, hepatitis B virus; INSTI, integrase strand transfer inhibitor; NRTI, nucleoside reverse transcriptase inhibitor. 1. USDHHS Guidelines for Use of ARV Agents in Adults and Adolescents with HIV 2018 October; 2. EACS Guidelines Version 9.1 2018 October; 3. Saag MS, et al. JAMA 2018;320:379-96; 4. Andreatta K, et al. CROI 2019, abstr 506.

  4. Study DesignStudy 380-4030 Primary Endpoint • Week 0 48 • Phase 3, randomized, double-blind, active-controlled study • Documented or suspected NRTI, NNRTI and PI resistance permitted • Randomization stratified by known or suspected NRTI resistance category at baseline • 1) K65R or ≥3 TAMS; 2) other NRTI mutations; 3) no known NRTI resistance • Primary endpoint: proportion with HIV-1 RNA ≥50 c/mL at Week 48 • Noninferiority margin of 4% based on FDA snapshot algorithm • Adults with HIV on DTG + F/TAFor DTG + F/TDF • HIV-1 RNA <50 c/mL for ≥3 or 6 mo* • eGFRCG ≥30 mL/min • No known INSTI resistance • No prior virologic failure on INSTI B/F/TAF qd n=284 DTG + F/TAF placebo qd N=565 1:1 DTG + F/TAF qd n=281 B/F/TAF Placebo qd *3 months in participants with no known NRTI resistance mutations, 6 months in participants with known or suspected NRTI resistance. c, copies; eGFRCG, estimated glomerular filtration rate by Cockcroft-Gault equation; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; TAM, thymidine analogue mutation; TDF, tenofovir disoproxil fumarate.

  5. Participant Disposition From Baseline to Week 48Study 380-4030 Screened, n=633 Screen failures, n=44 Met eligibility criteria but not randomized, n=22* Randomized, n=567 Randomized and not treated, n=2 B/F/TAF n=284 DTG + F/TAF n=281 Randomized and treated Still on treatment n=261 Still on treatment n=252 *Lost to follow-up (n=5), withdrew consent (n=11), investigator’s discretion (n=2), enrollment closed (n=1), other reasons (n=3).AE, adverse event; D/C, discontinuation.

  6. Baseline CharacteristicsStudy 380-4030 IQR, interquartile range.

  7. Pre-existing NRTI Resistance Testing and StratificationStudy 380-4030 Historical Genotype HIV-1 RNA ≥400 c/mL 50% (285/565) ProviralDNA (GenoSure Archive) HIV-1 RNA <50 c/mL 69% (391/565) Any Genotype Data 83% (470/565) = & TAMs are M41L, D67N, K70R, L210W, T215F/Y, and K219Q/E/R/N. • Stratification for randomization was based on historical genotypes and investigator assessment of suspected resistance • Final analysis resistance categorization added data from proviral DNA testing

  8. Pre-existing NRTI ResistanceStudy 380-4030 • For more details on the resistance mutations in study 380-4030, see poster MOPEB241 *20 participants stratified to categories 1 or 2 based on investigator-suspected NRTI resistance (19 participants category 2, and 1 participant category 1); †Includes K65R/E/N, or ≥3 TAMs that include M41L or L210W, or T69 insertions; ‡Includes only M184V/I mutations confirmed by genotype.

  9. Virologic Outcome at Week 48Study 380-4030 Virologic Outcome by FDA Snapshot Treatment Difference in % Participants With HIV-1 RNA ≥50 c/mL (95.001% CI) • Switching to B/F/TAF was noninferior to remaining on DTG + F/TAF • No participant with pre-existing NRTI resistance had HIV-1 RNA ≥50 c/mL in either group Favors B/F/TAF Favors DTG + F/TAF B/F/TAF (n=284) DTG+ F/TAF (n=281) Participants, % HIV-1 RNA≥50 c/mL HIV-1 RNA<50 c/mL No Virologic Data  1  284  3  281 265 284 256 281  18  284  22  281 CI, confidence interval.

  10. Sensitivity Analysis for Low-level ViremiaStudy 380-4030 Virologic Outcome HIV-1 RNA <20 c/mL by FDA Snapshot • Undetectable HIV-1 RNA (target not detected) by overall B/F/TAF 64.1% vs DTG +F/TAF 60.5% • Analysis of undetectable HIV-1 RNA (target not detected) was consistent across each resistance category B/F/TAF (n=284) DTG+ F/TAF (n=281) Participants, % Overall K65R or ≥3 TAMs* Other NRTI resistance No NRTI resistance No M184V/I M184V/I ± other resistance 257 284 241 281 15 16 13 14 48 55 46 53 194 213 182 214 216 237 212 247 41 47 29 34 *Includes K65R/E/N, or ≥3 TAMs that include M41L or L210W, or T69 insertions.

  11. Resistance AnalysisStudy 380-4030 • No participant developed treatment-emergent resistance through Week 48 • Resistance analysis population includes any participant with virologic rebound • Confirmed virologic failure without resuppression • Two consecutive HIV-1 RNA tests ≥50 c/mL and HIV-1 RNA ≥200 c/mL at the confirmation test • HIV-1 RNA ≥200 c/mL at Week 48 or last visit on study drug (did not require confirmation) • The second, confirmatory sample was sent for resistance analysis, unless there was no follow-up sample

  12. Predictors of Pre-existing NRTI ResistanceStudy 380-4030 • Independent factors associated with NRTI mutations and M184V/I include a longer time since starting ART (10% per year), prior PI-containing regimen, Black race, and PI or NNRTI resistance • M184V/I was present in 42% with PI resistance and 35% with NNRTI resistance

  13. Adverse Events Leading to Study Drug DiscontinuationStudy 380-4030 • No participant discontinued due to pregnancy *Reported as treatment-related. Parentheses indicate day of study drug discontinuation.

  14. DeathsStudy 380-4030 *Reported as treatment emergent; †Occurred 3 months after discontinuation of study drug and is not classified as treatment emergent.

  15. Most Common Adverse Events Through Week 48Study 380-4030

  16. Laboratory Abnormalities Through Week 48Study 380-4030 LDL, low-density lipoprotein.

  17. Changes From Baseline in Fasting Lipids at Week 48Study 380-4030 Fasting Lipid Component Total Cholesterol LDL Cholesterol HDL Cholesterol Triglycerides Total Cholesterol:HDL -1 -1 0 -0.1 0 +1 +4 +3 Median, mg/dL Median 3.9 3.7 +1 0 There was no difference between treatment arms in the changes from baseline in fasting lipids at Week 48 Similar percentages were on lipid-lowering agents at baseline: B/F/TAF 21%, DTG + F/TAF 21%, p=0.92; or initiated lipid-lowering agents during the study: B/F/TAF 4.6%, DTG + F/TAF 3.2%, p=0.52* Weight change from baseline at Week 48: B/F/TAF 1.3 kg, DTG + F/TAF 1.1 kg, p=0.46* • Baseline F/TDF 2.2 kg; baseline F/TAF 0.6 kg, with no difference in weight gain between B/F/TAF and DTG + F/TAF arms *p-value from Fisher exact test. LDL, low-density lipoprotein. HDL, high-density lipoprotein.

  18. Conclusions Study 380-4030 • For people with HIV on DTG + either F/TAF or F/TDF, switching to B/F/TAF was noninferior to DTG + F/TAF, with high rates of virologic suppression regardless of pre-existing NRTI resistance • 93.3% B/F/TAF vs 91.1% DTG + F/TAF had HIV-1 RNA <50 copies/mL at Week 48 • No participant with pre-existing NRTI resistance had HIV-1 RNA ≥50 c/mL at Week 48 (see poster MOPEB241 for more details on resistance) • No treatment-emergent resistance was observed in either arm • NRTI resistance at baseline, including M184V/I, was associated with a longer duration of ART, a prior PI-containing regimen, Black race, and baseline PI or NNRTI resistance • There were no significant differences in adverse events, changes in fasting lipids, or changes in weight between groups

  19. 380-4030 Investigators Austria A. Rieger Canada J. Brunetta J.J. de Wet K. Kasper B. Lebouche S. Shafran B. Trottier France L. Cotte P-M. Girard J-M. Molina P. Morlat G. Pialoux P. Pugliese J. Reynes Y. Yazdanpanah Germany K. Arasteh A. Baumgarten M. Bickel O. Degen S. Esser C. Lehmann J.K. Rockstroh H-J Stellbrink C. Stephan United States J. Adams H. Albrecht P. Benson M. Berhe C. Brinson T. Campbell A. Colson P. Cook D.R. Coulston G. E. Crofoot F.A. Cruickshank E. DeJesus C. Dietz H. Edelstein R. Elion J .Flamm J. E. Gallant J. C. Gathe D. Goldstein R. Grossberg D. Hagins C.B. Hare K. Henry M. Iandiorio D. Jayaweera D. Klein A. LaMarca N. Lin A. Luetkemeyer C.T. Martorell C. Mayer J. P. McGowan M. McKellar E. Meissner A. Mills J.O. Morales-Ramirez C. Newman G. Oguchi O. Osiyemi P. Peyrani G. Pierone R. Pollard D.J. Prelutsky M.N. Ramgopal F. Rhame G.J. Richmond A. Roberts P.J. Ruane J.L. Santana-Bagur L. Santiago P.E. Sax S. Schrader A. Scribner G.E. Sepulveda-Arzola P. Shalit C. M. Shikuma J. Slim M.S. Somero D. Stein J.L. Stephens M.A. Thompson T. Treadwell T. Vanig G.Voskuhl B.H. Wade D.J. Ward A. Wilkin D.A. Wohl M. Wohlfeiler K. Workowski A.K. Wurapa B.G. Yangco

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