Presentation on theme: "Huyen Cao9, Marshall Fordyce9"— Presentation transcript:
1 Huyen Cao9, Marshall Fordyce9 Renal and Bone Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate Combined Safety Results of Studies GS-US and GS-USPaul Sax1, Michael Saag2, Michael Yin3, Frank Post4, Shinichi Oka5, Ellen Koenig6, Benoit Trottier7, Jaime Andrade-Villanueva8,Huyen Cao9, Marshall Fordyce91Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; 2University of Alabama Birmingham, Birmingham, AL; 3College of Physicians and Surgeons, Columbia University, New York, NY; 4King’s College, London, UK; 5National Center for Global Health and Medicine, Tokyo, Japan; 6Dominican Institute for Virologic Studies, Santo Domingo, Dominican Republic; 7Clinique Medicale L’Actuale in Montreal, Montreal, Canada; 8Unidad de VIH del Hospital Civil de Guadalajara, Guadalajara, Mexico; 9Gilead Sciences, Foster City, CAAbstract 143LB
2 Author DisclosuresDr. Sax has served as a consultant or Scientific Advisory Board member for Gilead Sciences, AbbVie, BMS, GSK/ViiV, Merck, and Janssen, and his institution, Harvard Medical School/Brigham and Women’s Hospital, has received support from Gilead Sciences, BMS, GSK/ViiV, and Merck
4 BackgroundAlthough potent and generally well tolerated, tenofovir disoproxil fumarate (TDF) may cause clinically significant renal and bone toxicity1-3Relative to TDF 300 mg, TAF 25 mg has 90% lower circulating plasma TFV, while maintaining high antiviral activity4In a phase II comparative study, TAF associated with reduced renal and bone effects5We sought to confirm these findings in fully powered clinical trials using extensive protocol-specified renal and bone endpointsVirologic efficacy of E/C/F/TAF non-inferior to E/C/F/TDF (Wohl # 113-LB)E/C/F, elvitegravir, cobicistat, emtricitabine.1. Mocroft AIDS Jul 17;24(11): ; 2. Morlat PLoS One. 2013;8:e66223; 3. Mccomsey J Infect Dis. 2011;203: ;4. Ruane P, et al. JAIDS 2013; 63:449-54; 5. Sax PE.. et al. JAIDS 2014;67:52-58
5 Study Design: Studies 104 and 111 Primary Endpoint4814496Weekn=866E/C/F/TAF QDTx-Naïve AdultsHIV-1 RNA ≥1000 c/mLeGFR ≥50 mL/min1:1E/C/F/TDF QD (Stribild, STB)n=867Two Phase 3 randomized, double-blind, double-dummy, active-controlled studiesStudy 104 (North America, EU, Asia), Study 111 (North America, EU, Latin America)Stratified by HIV-1 RNA, CD4 cell count, geographic regionPrimary endpoint: proportion of patients with HIV-1 RNA <50 copies/mL (Taqman 2.0)Non-inferiority (12% margin) based on Week 48 FDA snapshot analysisCombined efficacy analysis pre-specifiedPre-specified Week 48 safety endpoints: serum creatinine, proteinuria, hip BMD, spine BMD5
7 Mean TFV Concentration, ng/mL (SD) Plasma TFV and Intracellular TFV-DP Levels Studies 104 and 111: Week 48 Combined AnalysisPlasma TFVIntracellular TFV-DP20Geometric mean (95% CI)E/C/F/TDF (n=29)E/C/F/TAF (n=36)154.1 XMean TFV Concentration, ng/mL (SD)TFV Exposure (μM*h)105XE/C/F/TDF(n=14)E/C/F/TAF(n=21)Time (h)Steady State TFV PKE/C/F/TDF n=29E/C/F/TAF n=36% ReductionMean AUCtau, ng*h/mL (%CV)3,410 (25)297(20)91
8 Mean (SD) Change from Baseline eGFR* Change in eGFR (Cockcroft-Gault) Studies 104 and 111: Week 48 Combined AnalysisMean (SD) Change from Baseline eGFR*-6.6p <0.001-11.2Time (Weeks)*Cockroft-Gault (mL/min).
9 Renal Adverse Events and Tubulopathy Studies 104 and 111: Week 48 Combined Analysis E/C/F/TAF n=866E/C/F/TDF n=867EventsRenal adverse events leading to discontinuation4 (0.5)*Tubulopathy/Fanconi syndromeLaboratory AbnormalitiesSubclinical tubulopathy†1 (0.1)Serum creatinine (≥0.4 mg/dL increase)Hypophosphatemia (≥1 grade decrease)3 (0.3)4 (0.5)Normoglycemic glycosuria (≥1 grade increase urine glucose; serum glucose ≤100 mg/dL)2 (0.2)Proteinuria (≥2 grade increase)*Renal failure (2), decreased GFR (1), nephropathy (1). †Confirmed abnormality in any 2 categories at 2 consecutive post-baseline visits.
10 Urine [protein]:Creatinine Ratio Retinol Binding Protein Changes in Quantitative Proteinuria at Week 48 Studies 104 and 111: Week 48 Combined AnalysisUrine [protein]:Creatinine RatioProtein (UPCR)Albumin (UACR)Retinol Binding ProteinBeta2- microglobulin76133168E/C/F/TAFE/C/F/TDFMedian % Change from Baseline (Q1, Q3)p <0.001for all57Baseline44mg/g5mg/g64μg/g67 μg/g101μg/g103 μg/g
11 Changes in Spine and Hip BMD Through Week 48 Studies 104 and 111: Week 48 Combined Analysis ‒0.66‒1.30Mean (SD) % Changefrom Baseline‒2.86‒2.952448Week2448WeekE/C/F/TAF, n845E/C/F/TDF, n850797816784773836848789815780767
12 BMD Categorical Changes at Week 48 Studies 104 and 111: Week 48 Combined Analysis ≥3% gainBMD ChangeSpineHipGain or loss <3%≥3% lossE/C/F/TAF (N=845)E/C/F/TDF (N=850)
13 Fasting Lipids at Week 48 Studies 104 and 111: Week 48 Combined Analysis E/C/F/TAFBaselineWeek 48E/C/F/TDF1891773.73.7115114109108Median Values (mg/dL)5148Total CholesterolLDLHDLTriglyceridesTC:HDL Ratiop < p < p < p= p=0.84Patients initiating lipid-modifying medications: 3.6% E/C/F/TAF vs 2.9% E/C/F/TDF (p=0.42).
14 Conclusions Studies 104 and 111: Week 48 Combined Analysis In these two large randomized clinical trials, detailed protocol-specified renal and bone endpoints confirmed the favorable safety and tolerability profile of TAFCompared with TDF, TAF demonstrated:No discontinuations due to renal AEsSignificantly smaller decreases in eGFRSignificantly less proteinuria, albuminuria, and tubular proteinuriaSignificantly less impact on spine and hip BMDGreater increases in fasting lipids, TC:HDL sameThe most likely explanation for these findings is the 90% lower tenofovir plasma exposure with TAF vs TDF
15 Additional DataStudy primary results presented Feb 25th (Wohl, 113LB)E/C/F/TAF non-inferior to E/C/F/TDF at Week 48 (92.4% vs 90.4%)Treatment-emergent resistance <1% in both armsBoth drugs well tolerated through 48 weeksPatients with mild to moderate renal impairment (eGFR mL/min) who switch to E/C/F/TAF improve BMD and markers of kidney function through 48 weeks (Pozniak, Poster #795)Complete results of Studies 104 and 111 submitted for peer-reviewed publicationHealth authority filings submitted and under review in multiple countries
16 AcknowledgmentsWe extend our thanks to the patients, their partners and families, and all participating Study 104 & 111 investigatorsC Achenbach, F Ajana, B Akil, H Albrecht, J Andrade Villanueva, J Angel, A Antela Lopez, J Arribas Lopez, A Avihingsanon, D Baker, J-G Baril, D Bell, N Bellos, P Benson, J Berenguer, I Bica, A Blaxhult, M Bloch, P Brachman, I Brar, K Brinkman, C Brinson, B Brown, J Brunetta, J Burack, T Campbell, M Cavassini, A Cheret, P Chetchotisakd, A Clarke, B Clotet, N Clumeck, C Cohen, P Cook, L Cotte, D Coulston, M Crespo, C Creticos, G Crofoot, F Cruickshank, J Cunha, E Daar, E DeJesus, J De Wet, M Doroana, R Dretler, M Dube, J Durant, H Edelstein, R Elion, J Fehr, R Finlayson, D Fish, J Flamm, S Follansbee, H Furrer, F Garcia, J Gatell Artigas, J Gathe, S Gilroy, P-M Girard, J-C Goffard, E Gordon, P Grant, R Grossberg, C Hare, T Hawkins, R Hengel, K Henry, A Hite, G Huhn, M Johnson, M Johnson, K Kasper, C Katlama, S Kiertiburanakul, JM Kilby, C Kinder, D Klein, H Knobel, E Koenig, M Kozal, R Landovitz, J Larioza, A Lazzarin, R LeBlanc, B LeBouche, S Lewis, S Little, C Lucasti, C Martorell, C Mayer, C McDonald, J McGowan, M McKellar, G McLeod, A Mills, J-M Molina, G Moyle, M Mullen, C Mussini, R Nahass, C Newman, S Oka, H Olivet, C Orkin, P Ortolani, O Osiyemi, F Palella, P Palmieri, D Parks, A Petroll, G Pialoux, G Pierone, D Podzamczer Palter, C Polk, R Pollard, F Post, A Pozniak, D Prelutsky, A Rachlis, M Ramgopal, B Rashbaum, W Ratanasuwan, R Redfield, G Reyes Teran, J Reynes, G Richmond, A Rieger, B Rijnders, W Robbins, A Roberts, J Ross, P Ruane, R Rubio Garcia, M Saag, J Santana- Bagur, L Santiago, R Sarmento e Castro, P Sax, B Schmied, T Schmidt, S Schrader, A Scribner, S Segal- Maurer, B Sha, P Shalit, D Shamblaw, C Shikuma, K Siripassorn, J Slim, L Sloan, D Smith, K Squires, D Stein, J Stephens, K Supparatpinyo, K Tashima, S Taylor, P Tebas, E Teofilo, A Thalme, M Thompson, W Towner, T Treadwell, B Trottier, T Vanig, N Vetter, P Viale, G Voskuhl, B Wade, S Walmsley, D Ward, L Waters, D Wheeler, A Wilkin, T Wilkin, E Wilkins, T Wills, D Wohl, M Wohlfeiler, K Workowski, B Yangco, Y Yazdanpanah, G-P Yeni, M Yin, B Young, A Zolopa, C ZurawskiThis study was funded by Gilead Sciences, Inc.