1. Microbicides and PrEP: Back to Basics Wednesday July 25, 2012 ADM Kashuba

2. Drug Exposure Predicts Efficacy SC or PO tenofovir±emtricitabine Multiple Routes of Viral Challenge Vaginal Challenge TFV 30mg/kg/d SC Otten 2000 No Protection Monkey Plasma Concentration Relative to Human Exposure Partial Protection Full Protection Rectal Challenge TFV 22mg/kg/d PO Subbarao 2006 Rectal Challenge TFV 22 + FTC 20mg/kg/d SC Garcia Lerma 2008 Rectal Challenge TFV 22 + FTC 20mg/kg/d PO Garcia Lerma 2010 Rectal Challenge TFV 10mg/kg/d PO Van Rompay 2006 Oral Challenge TFV 10mg/kg/d PO Van Rompay 2006 Oral Challenge TFV.04 mg/kg/d PO Van Rompay 2002 Oral Challenge TFV.02 mg/kg/d PO Van Rompay 2006 Oral Challenge TFV 30 mg/kg/d SC Van Rompay 2001 Oral Challenge TFV 30 mg/kg/d SC Van Rompay 1998 IV Challenge TFV 30 mg/kg/d SC Tsai 1995 100X 3X “Lower”

3. Adherence Predicts Efficacy Drugs only Work If They Are Used: HPTN 052 Immediate Arm Delayed Arm (not on ART) Delayed Arm (on ART) Cohen et al. MOAXO102, 6 th IAS Conference, Rome, Italy, 2011 90%

4. Efficacy with Modest Adherence to TDF/FTC in MSM (iPrEx) TFV- DP CONC iPrEx Case-Control Analysis STRAND (Directly-Observed TDF Dosing ) CasesControls2 doses/wk 4 doses/wk 7 doses/wk N4814421 22 % drug detected 8%44% 56% < 2 doses/wk; 18% in range of daily dosing 100% Anderson, Liu et al. CROI 2012 ???

5. Infection with (Seemingly) Good Adherence (Partners PrEP) Donnell et al. CROI 2012 Detectable Drug Conc. Cases (TDF=17, TDF/FTC=12) Cohort (n=198) Seroconversion VisitsAll visits TDF arm 6/1731%363/43783% TDF/FTC arm 3/1225%375/46681% TFV Plasma Concentration (ng/mL) >40ng/mL Visit Months 0 3 6 9 12 15 18 21 24 27 30 ???

6. The Relationship Between Pharmacokinetics (drug exposure) & Pharmacodynamics (drug target) Can Alter The Importance of Adherence Minimum Effective Concentration Days Concentration Q Day Q Week The Principles of PrEP

7. TDF vs TFV 1% Gel in Women Concentrations Differ With Formulation TFV 1% Gel Vaginal Lumen TDF Tablet Vaginal Lumen Schwartz et al PloS One, 2011; Dumond et al AIDS 2008 100-1000x Abdool-Karim et al, Lancet 2011 Placebo gel TFV Gel ≤ 1,000ng/mL TFV Gel > 1,000ng/mL

8. Do different formulations act differently? Are target concentrations different for topical versus systemic delivery? Chuchuen et al M2011 TFV 1% Gel TDF vs TFV 1% Gel in Women Lumen, Tissue, Regional Lymph Nodes Plasma TDF 300mg MUSCULARIS

9. TDF/FTC and Colorectal Tissue ARV Concentrations Differ Compared to Cervicovaginal Tissue Patterson et al Sci Transl Med, 2011 FTC Rectal Tissue FTC Vaginal Tissue TFV Rectal Tissue TFV Vaginal Tissue Implications for Efficacious Dosing Depending on Surface to be Protected At 24h: Colorectal TFV-DP ~200 fmol/mg Vaginal TFV-DP ~1 fmol/mg

10. TDF vs TFV 1% Gel in Colorectal Tissue Concentrations Less Divergent With Different Formulations? Anton et al CROI 2011 30min 24h Patterson et al 2011 ORAL DOSE TOPICAL DOSE

11. Minimum Effective Concentration Days Concentration Oral TDF Dosing for Cervicovaginal Protection Requires high daily (eg>80%) adherence Oral TDF/FTC Dosing for Colorectal Protection Topical TFV Dosing for Cervicovaginal Protection Less than Daily Adherence May Provide Protection (≤ 2x/wk; BAT24) An Intricate Relationship Exists Between Pharmacokinetics, Pharmacodynamics, and Adherence in PrEP To be determined: Effect of inflammation & other physiologic factors on PK-PD-Adherence Relationship; Relationship Between Drug Exposure and MEC for New Drugs in Vaginal Rings, LAIs, etc