The Role of TAF in PrEP KATY GARRETT, PHARMD UNIVERSITY OF NORTH CAROLINA Dr. Garrett has nothing to disclose
Outline PrEP Efficacy Adherence among populations Pharmacokinetic and pharmacodynamics relationship to adherence TAF pharmacology TAF s role in PrEP by risk group Receptive vaginal intercourse Receptive anal intercourse Injection drug use
PrEP Clinical Efficacy Partners PrEP Population Drug Overall Efficacy 1,785 heterosexual women in serodiscordant relationships TDF 71% (37-87) FTC/TDF 66% (28-84) FEM-PrEP 2,120 heterosexual women FTC/TDF 6% (-52-41) VOICE Partners PrEP 5,029 heterosexual women 2,962 males in serodiscordant heterosexual relationships TDF -49% (-129-3) FTC/TDF -4% (-49-27) TDF 63% (20-83) FTC/TDF 84% (54-94) iprex 2,499 MSM/TGW (59% unprotected receptive anal intercourse) FTC/TDF 44% (15-63) IPERGAY 400 MSM/TGW FTC/TDF On-Demand 86% (40-98) Bangkok Tenofovir Study 2,413 PWID TDF 49% (9.6-72) Baeten JM, et al. Lancet ID. 2014 Nov;14; Van Damme L, et al. N Engl J Med. 2012 Aug 2; Molina JM, et al. N Engl J Med. 2015. Dec 3; Marrazzo JM, et al. N Engl J Med. 2015 Feb 5;Grant RM, et al. N Engl J Med. 2010. Dec 30; Choopanya K, et al. Lancet. 2010. Dec 30
PrEP Clinical Efficacy Population Drug Overall Efficacy Partners PrEP 2,962 heterosexual men in serodiscordant relationships TDF 63% (20-83) FTC/TDF 84% (54-94) iprex 2,499 MSM/TGW (59% unprotected receptive anal intercourse) FTC/TDF 44% (15-63) IPERGAY 400 MSM/TGW FTC/TDF On-Demand 86% (40-98) Bangkok Tenofovir Study 2,413 PWID TDF 49% (9.6-72) Baeten JM, et al. Lancet ID. 2014 Nov;14; Van Damme L, et al. N Engl J Med. 2012 Aug 2; Molina JM, et al. N Engl J Med. 2015. Dec 3; Marrazzo JM, et al. N Engl J Med. 2015 Feb 5;Grant RM, et al. N Engl J Med. 2010. Dec 30; Choopanya K, et al. Lancet. 2010. Dec 30
PrEP Clinical Efficacy Population Drug Overall Efficacy Bangkok Tenofovir Study 2,413 PWID TDF 49% (9.6-72) Baeten JM, et al. Lancet ID. 2014 Nov;14; Van Damme L, et al. N Engl J Med. 2012 Aug 2; Molina JM, et al. N Engl J Med. 2015. Dec 3; Marrazzo JM, et al. N Engl J Med. 2015 Feb 5;Grant RM, et al. N Engl J Med. 2010. Dec 30; Choopanya K, et al. Lancet. 2010. Dec 30
Efficacy (%) Modified AVAC Infographic PrEP Works If you Take It Effectiveness and Adherence in Trials of Oral and Topical Tenofovir-Based Prevention Effectors of PrEP Efficacy--Adherence 100 80 60 40 20 0-20 -40 FEM-PrEP VOICE iprex IPERGAY Partner's PrEP (FTC/TDF) Partner's PrEP (TDF) Bangkok Tenofovir iprex FEM-PrEP VOICE (FTC/TDF) VOICE (TDF) -60 20 30 40 50 60 70 80 90 Percentage of Adherent Participants
Pharmacokinetics (PK) & Pharmacodynamics (PD) C max Effective Concentration T 1/2 C min AUC EC 90 =0.3
Hendrix CW. CROI 2014. Plasma TFV PD of PrEP Clinical Trials No relationship between plasma concentration and efficacy
Surrogates for Systemic PrEP Efficacy 76% Protection 96-99% Protection EC 90 rectal tissue equivalent 700 fmol/10 6 rectal mononuclear cells Anderson PL, et al. Sci Transl Med. 2012; 12:4(151);Patterson KB, et al. Sci Transl Med. 2011 Dec 7; 3(112); Cottrell ML, et al. J Infec Dis. 2016; 214(1)
Surrogates for Systemic PrEP Efficacy 76% Protection 96-99% Protection TFVdp (fmol/g) 10 7 10 6 10 5 10 4 10 3 Rectal AUC1-14D (fmol*d/g) Female Genital Tract 10 6 10 5 10 4 10 3 >100-fold lower EC 90 rectal tissue equivalent 700 fmol/10 6 rectal mononuclear cells 10 2 6 24 48 120 168 240 336 Time (hr) Anderson PL, et al. Sci Transl Med. 2012; 12:4(151);Patterson KB, et al. Sci Transl Med. 2011 Dec 7; 3(112); Cottrell ML, et al. J Infec Dis. 2016; 214(1)
Surrogates for Systemic PrEP Efficacy CD4+ Possible Surrogates TFVdp PBMC EC 90 (iprex) Freshly lysed PBMCs 37 (23-50) fmol/10 6 cells TFVdp rectal mononuclear cells EC 90 (iprex) 700 fmol/10 6 cells TFVdp:dATP EC 50 & EC 90 (in vitro) Molar Ratio = 0.09-0.29 Cottrell ML, et al. J Infec Dis. 2016; 214(1) Anderson PL, et al. Sci Transl Med. 2012; 12:4(151); Seifert S, et al. 15 th Clin. Pharmacology of HIV & Hepatitis Therapy 2014. Abstract 0_10
Adapted from Liu Y. Poster Number H-664, ICAAC 2013. TAF Pharmacology Optimizing the PK Profile 4-7-fold higher TFVdp concentrations in PBMCs 4-7-fold lower TFV concentrations in plasma GI Tract Plasma PBMCs TAF TDF TAF TAF TFV TFV TFV TFV TFV TFVmp TFVdp TFVmp TFVdp
Garrett KL, et al. CROI 2016. Abstract 102LB TAF s Pharmacokinetic Utility 1000 MINIMIZE ADVERSE REACTIONS PLASMA 1000 MAXIMIZE EFFICACY PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) TFV (ng/ml) 100 10 1 TDF 300mg TAF 25mg TFVdp (fmol/10 6 cells) 100 10 TAF 25mg TDF 300mg 0.1 0 6 12 24 48 72 Time (hr) 1 0 6 12 24 48 72 Time (hr)
Protecting the Target Population RECEPTIVE VAGINAL INTERCOURSE
TAF-Female Genital Tract Tissue TFV exposure 2-fold lower in FGT after 25mg TAF TFVdp exposure 1.3-fold lower in FGT after 25mg TAF TFVdp 75% BLQ in FGT after TAF 25mg (25% for TDF) TFV or TFVdp (pm) 10 5 10 4 10 3 TDF 300mg TAF 25mg TFVdp LLOQ 0 6 12 24 48 72 Time (hr) Garrett KL et al. CROI 2016. Abstract 102LB
Cottrell ML et al. J Infect Dis. 2016 Feb 24 Female Genital Tract Tissue -Simulations EC 90 =0.29 Only ~15-39% of population are protected with daily TDF dosing Unable to simulate with TAF due to minimally quantifiable TFVdp Expect less protection conferred by TAF secondary to tissue penetration EC 50 =0.09 TDF 300mg Data represent 5, 50, and 95 percentiles of simulated ratios
Protecting the Target Population RECEPTIVE ANAL INTERCOURSE
TAF-Rectal Tissue 10 7 TFV exposure 10-fold lower following TAF 25mg TFVdp exposure 13-fold lower following TAF 25mg TFVdp 63% BLQ in rectal tissue with TAF 25mg (0% for TDF) TFV or TFVdp (pm) 10 6 10 5 10 4 TDF 300mg TAF 25mg 10 3 TFVdp LLOQ 0 6 12 24 48 72 Time (hr) Garrett KL et al. CROI 2016. Abstract 102LB
Cottrell ML et al. J Infect Dis. 2016 Feb 24 Rectal Tissue-Simulations ~100% of population are protected with daily dosing of TDF Unable to simulate with TAF due to minimally quantifiable TFVdp Cannot extrapolate PBMC TFVdp to rectal tissue from macaque data EC 90 =0.29 EC 50 =0.09 TDF 300mg Data represent 5, 50, and 95 percentiles of simulated ratios
TAF Macaque Models-Rectal Transmission 13.7 mg/kg TAF 3 days prior to weekly SHIV exposure up to 14 weeks No difference in Protection Rate Garcia-Lerma JG, et al. J Virol. 2011 Jul;85(13):6610-17
TAF Macaque Models-Rectal Transmission 13.7 mg/kg TAF 3 days prior to weekly SHIV exposure up to 14 weeks No difference in Protection Rate EC 90 =50 Garcia-Lerma JG, et al. J Virol. 2011 Jul;85(13):6610-17
TAF Macaque Models-Rectal Transmission 13.7 mg/kg TAF 3 days prior to weekly SHIV exposure up to 14 weeks No difference in Protection Rate EC 90 =700 EC 90 =50 Garcia-Lerma JG, et al. J Virol. 2011 Jul;85(13):6610-17
TFVdp:dATP Ratio TFVdp:dATP Ratio TAF Macaque Models-Rectal Transmission Ratio in PBMCs above threshold Ratio in rectal mononuclear cells below threshold-cause for futility? 100 100 10 10 1 0,1 EC 90 =0.29 EC 90 =0.29 1 0,1 0,01 Total PBMC CD4+ CD14+ CD14-/CD16+ 0,01 ILN MLN ALN Total MNC CD4+ Rectal Tissue Garcia-Lerma JG, et al. J Virol. 2011 Jul;85(13):6610-17
TAF Macaque Models-Rectal Transmission TAF 1.5 mg/kg (with FTC) 24h prior and 2h after weekly SHIV challenge Same dosing strategy demonstrated 94% efficacy with FTC/TDF 100% Protection (n=6) (n=6) Massud I, et al. J Infect Dis. 2016 Oct 1;214(7):1058-62
TAF Macaque Models-Rectal Transmission TAF 1.5 mg/kg (with FTC) 24h prior and 2h after weekly SHIV challenge Same dosing strategy demonstrated 94% efficacy with FTC/TDF 100% Protection (n=6) (n=6) EC 90 =50 Massud I, et al. J Infect Dis. 2016 Oct 1;214(7):1058-62
TAF Macaque Models-Rectal Transmission TAF 1.5 mg/kg (with FTC) 24h prior and 2h after weekly SHIV challenge Same dosing strategy demonstrated 94% efficacy with FTC/TDF 100% Protection >10-fold lower than TDF study (n=6) (n=6) EC 90 =50 25% BLQ Massud I, et al. J Infect Dis. 2016 Oct 1;214(7):1058-62
Protecting the Target Population INJECTION DRUG USE
TAF-PBMC Comparison 9-fold higher AUC over 48 hours with 25mg TAF than 300mg TDF TAF 25mg doses result in TFVdp >50 fmol/10 6 cells from 3-24h 50% of concentrations at 72h after 25mg TAF drop below 50 fmol/10 6 cells 300mg TDF remains below target concentration over 48h 50EC 90 =50 25mg TAF 10mg TAF 5mg TAF 300mg TDF Garrett KL et al. CROI 2016. Abstract 102LB
TAF-PWID Simulations TDF alone maximally protects ~90% of population with daily dosing-after one week See poster P21.12LB at R4P on Wednesday for more detail, A PK/PD Model to Predict Effective HIV PrEP Dosing Strategies for IV Drug Users TAF Model in development Expect much higher percentage of population protected with TAF alone compared to TDF EC 90 =0.29 EC 50 =0.09 TAF 25mg TDF 300mg Data represent 5, 50, and 95 percentiles of simulated ratios
Conclusions Pharmacodynamic targets for PrEP still require validation Tissue ratio of TFVdp:dATP correlates with clinical trials and macaque model data TAF has potential for use in PrEP Vaginal - due to low TFVdp concentrations in tissue may require combination therapy Rectal - TAF s role alone uncertain, likely in combination with FTC based on macaque data Injection drug use - promising results for single-agent use TAF is not recommended for PrEP until more data are known
Current/Future Studies CDC Macaque Studies Vaginal SHIV challenge Rectal SHIV challenge with only TAF CONRAD human phase 1 multiple-dose PK study (NCT02904369) PK and PD Study of Oral F/TAF for HIV Prevention Gilead Sciences Phase 3 Clinical Trial (NCT02842086) A Phase 3, Randomized, double-blind study to evaluate the safety and efficacy of emtricitabine and tenofovir alafenamide (F/TAF) fixed-dose combination once daily for preexposure prophylaxis in men and transgender women who have sex with men and are at risk of HIV-1 infection Other formulations LA implant (Gunawardana M, et al. Antimicrob Agents Chemother. 2015)
Acknowledgements Virology Education organizers Kashuba Lab Angela Kashuba Mackenzie Cottrell Heather Prince Craig Sykes Amanda Schauer Funding Sources UNC Center for AIDS Research P30AI050410 Clinical Trials Research Center UL1TR001111 Gilead Sciences, Inc.