Transcript iPrEx Trial
Starting and Stopping PrEP: Lessons from Pharmacology David V. Glidden University of California at San Francisco IAS 2015, Vancouver 20 July 2015 [email protected] 1 A full bottle of questions How well does this work? What if I miss a day? How long before it works? How should I stop? So many considerations But does it matter that I’m “a top” “an injector” “trans man” “trans woman” “a cis woman”? 2 By Major HIV Exposure Site Dosing Tissue Concentration Efficacy 3 Pharmacokinetic Studies • PK studies in HIV- volunteers1,2,3 • Intracellular tenofovir (TFV-DP): blood (PBMC), rectal, vagina cells • FTC concentrates faster, shorter ½ life • TFV-DP concentrates in rectal cells1,2,3 10-100x > vaginal levels ≈ PBMC 1. Louissaint, et al., AIDS Hum. Ret. 2013 2. Patterson et al., Sci. Trans. Med. 2011 3. Anderson et al. 2012 4 Cervical v. Rectal Levels Anderson et al. 2012 Rectal Cells 1846 fmol/M (931-3659) Cervical Cells 194 fmol/M (20-1916) How much drug? where? when? how long? 5 Protective Concentration EC99 EC90 EC75 Anderson et al., Sci. Trans. Med. 2012 6 iPrEx Open Label No infections ≥ 4 tablets/week Grant et al, Lancet Inf. Dis. 2014 7 Cell PrEP Study • Daily TDF/FTC for 30 days • 19 HIV- volunteers – 10 female (5 Af. Am., 5 Cauc.) – 9 male (4 Cauc.,4 Af. Am.,1 Hisp.) • Blood at 1, 3, 7, 20, 30, 35, 45, 60d rectal/cervical sample at one visit • Intracellular levels TFV-DP, FTC-TP Seifert et al., Clin. Infect. Dis. 2015 8 Starting and Stopping For a (mostly) rectal exposed c-male, t-woman population PrEP Start Estimated Risk Reduction (CI) Median PBMC/ EC90 Dose 1 77% (40% to 93%) 0.58 Dose 2 89% (51% to 98%) 0.93 Dose 3 98% (60% to >99%) 1.37 Dose 4 98% (67% to >99%) 1.74 PrEP Stop (after 30 days of dosing) STOP +1d 97% (65% to >99%) 1.63 STOP + 3d 96% (64% to >99%) 1.43 STOP + 5d 93% (56% to 99%) 1.19 STOP + 7d 90% (52% to 99%) 1.00 Seifert et al., Clin. Infect. Dis. 2015 9 Ipergay • • • • MSM (rectally exposed) population 2 Dose 2-24h pre sex, 24h, 48h post Randomized, placebo controlled 86% efficacy: 14 Placebo v. 2 TDF/FTC both TDF/FTC HIV+ off drug for months • 16 tablets per month on average • Similar safety profile to daily use Molina et al. 2015 10 ADAPT Results • Comparable side effects by arms • Event driven uses 1/3 to 1/4 tablets Ipergay regimen would use~1/2 daily • CPT♀: daily much better coverage • ♂ in BKK: event-driven high coverage • ♂ in Harlem: daily slightly better coverage • Rectal exposed: 34 doses to protection, forgiveness 11 Summary • Ipergay: event-driven dosing biologically effective for rectally exposed pharmacology strongly supports it • Vaginal PK for coital dosing less favorable • ADAPT: “use effectiveness” in some MSM less favorable for some women • Need EC90 for vaginally exposed popn HIV w/pharmacology in demo projects 12 Megha Mehrotra Sybil Hosek Jaime Martinez Juan Guanira Carlos Mosquera Lorena Vargas Peter Anderson Sharon Seifert Lane Bushman Jose Castillo-Mancilla Grace Chow Ana Martinez