The Role of TAF in PrEP. Dr. Garrett has nothing to disclose

Transcription

1 The Role of TAF in PrEP KATY GARRETT, PHARMD UNIVERSITY OF NORTH CAROLINA Dr. Garrett has nothing to disclose

2 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

3 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 Nov;14; Van Damme L, et al. N Engl J Med Aug 2; Molina JM, et al. N Engl J Med Dec 3; Marrazzo JM, et al. N Engl J Med Feb 5;Grant RM, et al. N Engl J Med Dec 30; Choopanya K, et al. Lancet Dec 30

4 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 Nov;14; Van Damme L, et al. N Engl J Med Aug 2; Molina JM, et al. N Engl J Med Dec 3; Marrazzo JM, et al. N Engl J Med Feb 5;Grant RM, et al. N Engl J Med Dec 30; Choopanya K, et al. Lancet Dec 30

5 PrEP Clinical Efficacy Population Drug Overall Efficacy Bangkok Tenofovir Study 2,413 PWID TDF 49% (9.6-72) Baeten JM, et al. Lancet ID Nov;14; Van Damme L, et al. N Engl J Med Aug 2; Molina JM, et al. N Engl J Med Dec 3; Marrazzo JM, et al. N Engl J Med Feb 5;Grant RM, et al. N Engl J Med Dec 30; Choopanya K, et al. Lancet Dec 30

6 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 FEM-PrEP VOICE iprex IPERGAY Partner's PrEP (FTC/TDF) Partner's PrEP (TDF) Bangkok Tenofovir iprex FEM-PrEP VOICE (FTC/TDF) VOICE (TDF) Percentage of Adherent Participants

7 Pharmacokinetics (PK) & Pharmacodynamics (PD) C max Effective Concentration T 1/2 C min AUC EC 90 =0.3

8 Hendrix CW. CROI Plasma TFV PD of PrEP Clinical Trials No relationship between plasma concentration and efficacy

9 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 Dec 7; 3(112); Cottrell ML, et al. J Infec Dis. 2016; 214(1)

10 Surrogates for Systemic PrEP Efficacy 76% Protection 96-99% Protection TFVdp (fmol/g) Rectal AUC1-14D (fmol*d/g) Female Genital Tract >100-fold lower EC 90 rectal tissue equivalent 700 fmol/10 6 rectal mononuclear cells Time (hr) Anderson PL, et al. Sci Transl Med. 2012; 12:4(151);Patterson KB, et al. Sci Transl Med Dec 7; 3(112); Cottrell ML, et al. J Infec Dis. 2016; 214(1)

11 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 = 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 Abstract 0_10

12 Adapted from Liu Y. Poster Number H-664, ICAAC 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

13 Garrett KL, et al. CROI Abstract 102LB TAF s Pharmacokinetic Utility 1000 MINIMIZE ADVERSE REACTIONS PLASMA 1000 MAXIMIZE EFFICACY PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) TFV (ng/ml) TDF 300mg TAF 25mg TFVdp (fmol/10 6 cells) TAF 25mg TDF 300mg Time (hr) Time (hr)

14 Protecting the Target Population RECEPTIVE VAGINAL INTERCOURSE

15 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) TDF 300mg TAF 25mg TFVdp LLOQ Time (hr) Garrett KL et al. CROI Abstract 102LB

16 Cottrell ML et al. J Infect Dis 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

17 Protecting the Target Population RECEPTIVE ANAL INTERCOURSE

18 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) TDF 300mg TAF 25mg 10 3 TFVdp LLOQ Time (hr) Garrett KL et al. CROI Abstract 102LB

19 Cottrell ML et al. J Infect Dis 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

20 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 Jul;85(13):

21 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 Jul;85(13):

22 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 Jul;85(13):

23 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? ,1 EC 90 =0.29 EC 90 = ,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 Jul;85(13):

24 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 Oct 1;214(7):

25 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 Oct 1;214(7):

26 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 Oct 1;214(7):

27 Protecting the Target Population INJECTION DRUG USE

28 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 Abstract 102LB

29 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

30 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

31 Current/Future Studies CDC Macaque Studies Vaginal SHIV challenge Rectal SHIV challenge with only TAF CONRAD human phase 1 multiple-dose PK study (NCT ) PK and PD Study of Oral F/TAF for HIV Prevention Gilead Sciences Phase 3 Clinical Trial (NCT ) 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)

32 Acknowledgements Virology Education organizers Kashuba Lab Angela Kashuba Mackenzie Cottrell Heather Prince Craig Sykes Amanda Schauer Funding Sources UNC Center for AIDS Research P30AI Clinical Trials Research Center UL1TR Gilead Sciences, Inc.