1. Does Pharmacology Support Topical PrEP?
Angela DM Kashuba
UNC Eshelman School of Pharmacy
UNC Chapel Hill

2. Conflict of Interest UNC has received research funding from:
Gilead Sciences Inc
Merck Research Laboratories
GlaxoSmithKline
Consultant
Viiv Healthcare

3. Pharmacology Goals for Topical Prevention
Prevent HIV infection by delivering…..
1. the right drug(s)
2. to the right biological site(s)
3. at the right concentration(s)
4. for the right length of time
The challenge for using ARVs in prevention ….
There are many compounds developed, or in development for prevention, so let’s assume this is taken care of.

4. The Right Site Gel Covers Physical Location of Virus-sized Particles
Female Genital Tract Colorectal Tissue
Particles throughout lower GT (blue); ↑↑ around cervix/ fornices (yellow)
Gel ↑↑ around cervix/ fornices; lowest in lower vagina 24h post-dose
SPECT/CT
Particle exposure throughout lower GIT (blue); In some cases, up to splenic flexure.
Found along vagina with concentration at cervix
Can be seen up to splenic flexure
Extensive gel distribution 24h after administration
Hendrix et al Annu. Rev. Pharmacol. Toxicol :349
Shieh et al. AIDS Res Hum Retroviruses Jun 25
McGowan Expert Opinion on Drug Delivery, 11:1, 69-82

5. The Right Site Mucosal Exposure to Ring; High Concentrations at Cervix
Fuchs et al. AIDS Res Hum Retro 2015;32(11): 1109
Nel et al AIDS 2014;28:1479
Does the Drug Get to Sites of Infection?

6. The Right Site Early Events in HIV Infection: Location of Infection
Stroma
Stroma is a likely target to abort HIV infection
Do topicals get there?
Let’s move to the right site……
Fauci A. WAC 2010

7. The Right Site Concentrations Decline Across Tissue
Raman Spectroscopy; TFV 1% Gel
Maher et al. Biomet Opt Express 2015 May 8;6(6):
60min
DPV Ring in Sheep x 28d
Cryostat Tissues + LC-MS/MS
Hasn’t been done this way for rings but a method of taking tissue post necropsy and cryostating it into slices, and measuring the slices, in a sheep model, demonstrated similar findings.
120min
Are these concentrations adequate for efficacy?

8. The Right Concentration
Topical Gel in the Female GT and Male RT
Richardson-Harman et al PLoS One Oct 28;9(10):e111507
Yang et al PLoS One Oct 28;9(10):e106196
Schwartz et al Microbicides 2008
Schwartz et al IAS 2009
Rectal Gel Rectal Tissue
Rectal Gel Rectal Tissue
Topical exposure
Are the lowest of these concentrations
(100s-1000s) adequate for efficacy?

9. The Right Concentration TFVdp Concentration in Vaginal Tissues Versus Efficacy for TFV 1% Gel
Vaginal Gel Dosing 30min or 72h prior to Viral Exposure
30 min Post-Dose = 100% Protection
72h Post-Dose = 69% Protection
But is it the right concentration – macaque pk/pd study shows relationship
Pharmacologic Evidence for Gel Efficacy (although perhaps not at 100%)
Urvi et al J Virol 2009;83(20):10358
Dobard et al. J Virol 2012;86(2):718

10. The Right Concentration CAPRISA 004 (TFV 1% Gel)
Dobard et al. J Virol 2012;86(2):718
~200fmol/106cells TFVdp
EC 50 ~10,000 ng/mL
Andrei et al. Cell Host Microbe 2011 ;10(4): 379
When we look at the caprisa 004 study, it tells us….
TFV Conc-Effect Relationship for HIV and HSV2

11. The Right Concentration Tenofovir and Dapivirine Rings
IC90
DPV example; Conc high and sustained, with lower conc in lower vagina and introitus
TFV – DP concentrations in lymphocytes Lower conc
Vaginal fluids for three areas – introitus about 1 log lower.
At all three collection sites throughout the
28-day use period, including just prior to ring removal,
dapivirine vaginal fluid concentrations were at least
3900-fold the IC99 for dapivirine in a tissue explant
infection model (assuming a vaginal fluid density of
1 g/ml) [9,10]. Mean vaginal fluid dapivirine levels
obtained 24 h after ring removal, remained over 500-fold
higher than this inhibitory concentration.
BUT CVF 1 log greater than tissue……tissue conc 0.6ug/g
14d Post TDF IVR (130mg) in Pigtailed NHP
Nel et al AIDS 2014;28:1479
Chen et al. J Acquir Immune Defic Syndr. 2015; 70(3): 242
Smith et al. Proc Natl Acad Sci 2013;110(40):16145

12. The Right Time Concentrations After Last Dose: how long to protect tissue post-exposure?
TFV 1% Gel
DPV Ring
Not known how long protection should last after dosing, but replication competent virus found in cervical explant tissue up to 8 days
So if we assume a week, ……
Cvf 1 log greater than tissue
IC90
Prolonged TFV exposure
Long TFVdp t1/2
Short t1/2 after removal
CAPRISA 004 data, 2010

13. Does Pharmacology Support Topical PrEP?
Yes if…..
Formulation allows drug/metabolite distribution to viral locations
Drug/metabolite can penetrate deep into mucosal tissues (stromal concentrations)
Drug/metabolite achieves potent concentrations at these sites (eg above IC90?)
Drug/metabolite has long residence time to cover residual virus
Caveats
Can virus be trafficked to lymph nodes?
where drug concentrations from topical administration will remain low (“ceiling effect”)
Do inflammatory processes overwhelm the activity of standard doses/dose frequencies?
Might other sources of pharmacologic variability exist (eg microbiome)?
Right site
Right conc
Right time