Department Name

An exploration of adherence measures

to detect recent changes in Truvada ®

dosing patterns

Daijha JC Anderson, PharmD, Heather MA Prince, PA-C, Amanda Poliseno,

BS, Kristen Moody, PharmD, Ashley Saunders, PharmD candidate, Craig

Sykes, MS, Amanda P Schauer, BS, Brian Van Horne, BS, Katie Mollan, MS,

PhD candidate, Angel D Davalos, PhD candidate, Michael G Hudgens, PhD,

and Angela DM Kashuba, BScPhm, PharmD, DABCP, FCP

University of North Carolina Chapel Hill

Disclosures – Daijha JC Anderson

2Department Name

No conflicts of interests

Relations possible relevant to this

meeting:

None

Sponsoring & Research grants NIH Grant #: R01 AI 122319

CFAR grant #: P30 AI50410

Consultation fees: None

Stock shareholder: None

Other support: Pharmaceutical Product Development

(PPD) sponsored Drug Development

and Clinical Research fellowship

3Department Name

• Adherence to Truvada® and valid measures of

adherence are crucial for the success of PrEP.

• Measured concentrations in various blood

sample matrices have been used as objective

measures of adherence.1

Background

1.) Fonner, VA et al. AIDS . 2016 Jul31; 30(12):1973–83.2.) Patterson, KB et al. Sci Transl Med. 2011 Dec 7;3(112):112re4

3.) Brooks KM and Anderson PL. Clin Pharmacol Ther. 2018 Dec;104(6):1056-1059

TFVdp FTCtp

PBMCs 6 days 1.6 days

RBCs 17 days 1.5 days

TFV FTC

Plasma 17 hours 10 hours

1-2 months3

TFVdp in RBC1-2 weeks3

TFVdp in PBMCs1-7 days2

Parent drugs in plasma

Half-lives

Adherence Over Time

UNC ENLIGHTEN study: (Establishing Novel Antiretroviral Imaging for Hair To End Nonadherence)

4

Secondary Objective1. Assess the ability of blood matrices to discriminate changes in

Truvada® dosing patterns within one month. Mitra

Primary Objective

1. Assess dose-proportionality of tenofovir/emtricitabine (TDF/FTC)

maraviroc (MVC), and dolutegravir (DTG) in hair compared to:

a) Plasma

b) Peripheral Blood Mononuclear Cells (PBMCs)

c) Upper Layer Packed Cells (ULPCs)

d) Dried Blood Spots (DBS)

e) Whole blood microsamplers (Mitra)

NCT03218592

Methods: Study Allocation Scheme

5

Single Dose

on Day 0Daily Dosing

Dose

Proportionality

Single-center, open-label, 3-arm, directly observed therapy, triple phase study

Study Site: UNC Clinical & Translational Research Center (CTRC) Chapel Hill, NC

0

(n=4)

Doses/Week

1

(n=4)

3

(n=4)

Phase 1:

28 days

Phase 2:

28 days

Phase 3:

28 days

Days 3, 7, 14, 21, 28:

Hair Samples, Plasma, PBMC, ULPC, DBS, Mitra

and Adverse Event Monitoring

NCT03218592

Tenofovir/

emtricitabine

(n=12)

Methods: Data Analysis

6

• TFV and FTC (measured in the plasma), and TFVdp and FTCtp (measured in cells)

by LC-MS/MS.

1.) Patterson, KB et al. Sci Transl Med. 2011 Dec 7;3(112):112re4

2.) Cottrell, ML et al. J Infect Dis. 2016 Jul 1;214(1):55-64

3.) Adams, JL et al. J Acquir Immune Defic Syndr. 2013 Mar 1;62(3):260-6

LLOQPlasma

(ng/mL)1

PBMC

(ng/mL lysate)2

ULPC

(fmol/mL)3

DBS

(fmol/3mm punch)4

Mitra

(fmol/sample tip)5

TFV/TFVdp1.0 0.02

10,000100 300

FTC/FTCtp 5,000

- All BLQ values imputed as 0.5 * LLOQ

4.) Schauer, AP et al. J Pharm Biomed Anal. 2018 Feb 5;149:40-45

5.) Schauer, AP et al. Mass Spectrometry:Applications to the Clinical Lab

2019. Atlanta, GA. Abstract 296390. Poster MP067

• Concentrations reported as median (25th-75th percentile).

• Pearson correlations were used to described the dose-concentration response

relationship within each blood matrix (SigmaPlot®, v13.0).

• Dose-concentration effect was then evaluated using a tobit linear mixed effects model

predicting concentrations based on the number of doses per week (SAS/STAT®, v15.1).

– Target β estimate > 1.0

Results: Selecting Steady State Conditions

7

TFV/TFVdp Concentrations

after 28 days of Daily Dosing

FTC/FTCtp Concentrations

after 28 days of Daily Dosing

Assumed Css

Sampling Days

TFV and FTC TFVdp FTCtp

3 + 7 28 14 + 21 + 28

PlasmaPlasma

DBSDBS

PBMC

PBMC

MitraMitra

ULPC

ULPC

TFV in Plasma (t1/2 = 17 hrs)

Results: Plasma and PBMCs

8TFV = tenofovir FTC = emtricitabine

TFVdp = tenofovir diphosphate FTCtp = emtricitabine triphosphate

TFVdp in PBMC (t1/2 = 6 days)

TFV in Plasma

Phase 3Phase 2

7 doses/week (n=12)

3 doses/week (n=4)

1 dose/week (n=4)

0 doses/week (n=4)

7 doses/week (n=12)

3 doses/week (n=4)

1 dose/week (n=4)

0 doses/week (n=4)

Phase 3Phase 2

TFVdp in PBMC

TFV in Plasma (t1/2 = 17 hrs)

Results: Plasma and PBMCs

9TFV = tenofovir FTC = emtricitabine

TFVdp = tenofovir diphosphate FTCtp = emtricitabine triphosphate

FTC in Plasma (t1/2 = 10 hrs)

TFVdp in PBMC (t1/2 = 6 days) FTCtp in PBMC (t1/2 = 1.6 days)

β = 0.81 [95%CI: 0.64-0.98]

r = 0.85

β = 1.37 [95%CI: 1.25-1.48]

r = 0.95

β = 1.53 [95%CI: 1.20-1.86]

r = 0.92

β = 1.17 [95%CI: 1.07-1.28]

r = 0.95

Target β estimate > 1.0

10

Results: DBS

TFV = tenofovir FTC = emtricitabine

TFVdp = tenofovir diphosphate FTCtp = emtricitabine triphosphate

DBS = Dried Blood Spot

TFVdp in DBS (t1/2 = 17 days) FTCtp in DBS (t1/2 = 1.5 days)

β = 0.36 [95%CI: 0.25-0.46]

r = 0.72β = 0.92 [95%CI: 0.72-1.13]

r = 0.77

Target β estimate > 1.0

11

Results: ULPC and Mitra

TFV = tenofovir FTC = emtricitabine

TFVdp = tenofovir diphosphate FTCtp = emtricitabine triphosphate

ULPC = Upper Layer Packed Cells

Mitra = whole blood microsampler

TFVdp in ULPC (t1/2 = 17 days) FTCtp in ULPC (t1/2 = 1.5 days)

TFVdp in Mitra (t1/2 = 17 hrs) FTCtp in Mitra (t1/2 = 1.5 days)

β = 0.44 [95%CI: 0.35-0.52]

r = 0.84

β = 0.83 [95%CI: 0.71-0.94]

r = 0.89

β = 0.42 [95%CI: 0.25-0.59]

r = 0.63

β = 0.33 [95%CI: 0.17-0.49]

r = 0.62

Target β estimate > 1.0

Limitations

• Secondary endpoint was not powered as for our primary endpoints.

• Values were imputed for 0 doses/week for log transformation of data.

• Despite the use of the tobit linear mixed effects model because of left censoring due to

BLQ values, data were still non-linear in some matrices.

12

Conclusions

Intermediate half-lives TFVdp and FTCtp in PBMCs are best in detecting changes in

dosing patterns over one month.

If using DBS, FTCtp concentrations can be used for recent dosing. In this analysis:

- Concentrations < 300 fmol/3mm punch = taking < 7 doses/week

- Concentrations < 140 fmol/3mm punch = taking < 3 doses/week

13

TFV/TFVdp

β Estimate [95% CI]

TFV/TFVdp

Pearson’s r

FTC/FTCtp β

Estimate [95% CI]

FTC/FTCtp

Pearson’s r

PBMC 1.17 [1.07-1.28] 0.95 1.37 [1.25-1.48] 0.95

ULPC 0.42 [0.25-0.59] 0.63 0.83 [0.71-0.94] 0.89

DBS 0.36 [0.25-0.46] 0.72 0.92 [0.72-1.13] 0.77

Mitra 0.33 [0.17-0.49] 0.62 0.44 [0.35-0.52] 0.84

Acknowledgements:

14

Future Directions

• Exploring measuring both TFV and FTC concentrations, along with measuring

metabolite concentrations, in one DBS sample.

Sponsors:R01 AI122319; Division of AIDS, NIAID, US National Institutes of Health

P30 AI50410: UNC Center for AIDS Research, NIAID, US National Institutes of Health

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ENLIGHTEN Study Team

15Department Name

QUESTIONS?