Starting and Stopping PrEP: Lessons from

PharmacologyDavid V. Glidden

University of California at San Francisco

IAS 2015, Vancouver 20 July 2015

david.glidden@ucsf.edu

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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

By Major HIV Exposure Site

3Dosing Tissue Concentration Efficacy

Pharmacokinetic Studies

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• 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

2. Patterson et al., Sci. Trans. Med. 2011

1. Louissaint, et al., AIDS Hum. Ret. 2013

3. Anderson et al. 2012

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

Protective Concentration

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Anderson et al., Sci. Trans. Med. 2012

EC75

EC90

EC99

iPrEx Open Label

7Grant et al, Lancet Inf. Dis. 2014

No infections ≥ 4 tablets/week

Cell PrEP Study

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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

Starting and Stopping

9Seifert et al., Clin. Infect. Dis. 2015

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

For a (mostly) rectal exposed c-male, t-woman population

Ipergay

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• 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

ADAPT Results

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• 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

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

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Grace ChowAna Martinez

Sybil HosekJaime Martinez

Juan GuaniraCarlos Mosquera

Lorena Vargas

Megha Mehrotra

Peter Anderson Sharon SeifertLane Bushman

Jose Castillo-Mancilla