1. Starting and Stopping PrEP: Lessons from Pharmacology David V. Glidden University of California at San Francisco IAS 2015, Vancouver 20 July 2015 david.glidden@ucsf.edu 1

2. 2 How well does this work? How long before it works? What if I miss a day? But does it matter that I’m “a top” “an injector” “trans man” “trans woman” “a cis woman”? How should I stop? A full bottle of questions So many considerations

3. By Major HIV Exposure Site 3 Dosing  Tissue Concentration  Efficacy

4. Pharmacokinetic Studies 4 PK studies in HIV- volunteers 1,2,3 Intracellular tenofovir (TFV-DP): blood (PBMC), rectal, vagina cells FTC concentrates faster, shorter ½ life TFV-DP concentrates in rectal cells 1,2,3 10-100x > vaginal levels ≈ PBMC 2. Patterson et al., Sci. Trans. Med. 2011 1. Louissaint, et al., AIDS Hum. Ret. 2013 3. Anderson et al. 2012

5. Cervical v. Rectal Levels How much drug? where? when? how long? 5 1846 fmol/M (931-3659) 194 fmol/M (20-1916) Rectal Cells Cervical Cells Anderson et al. 2012

6. Protective Concentration 6 Anderson et al., Sci. Trans. Med. 2012 EC 75 EC 90 EC 99

7. iPrEx Open Label 7 Grant et al, Lancet Inf. Dis. 2014 No infections ≥ 4 tablets/week

8. Cell PrEP Study 8 Seifert et al., Clin. Infect. Dis. 2015 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

9. Starting and Stopping 9 Seifert et al., Clin. Infect. Dis. 2015 PrEP Start Estimated Risk Reduction (CI) Median PBMC/ EC 90 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 + 5d93% (56% to 99%) 1.19 STOP + 7d 90% (52% to 99%) 1.00 For a (mostly) rectal exposed c-male, t-woman population

10. Ipergay 10 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

11. ADAPT Results 11 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: 3- 4 doses to protection, forgiveness

12. 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 EC 90 for vaginally exposed pop n HIV w/pharmacology in demo projects 12

13. Grace Chow Ana Martinez Sybil Hosek Jaime Martinez Juan Guanira Carlos Mosquera Lorena Vargas Megha Mehrotra Peter Anderson Sharon Seifert Lane Bushman Jose Castillo-Mancilla