MTN-001 Phase 2 Adherence and Pharmacokinetic Study of Oral and Vaginal Preparations of Tenofovir

Craig Hendrix, Alexandra Minnis, Vijayanand Guddera, Sharon Riddler, Robert Salata, Clemensia Nakabiito, Craig Hoesley, Jessica Justman, Lydia Soto-Torres, Katherine Bunge, Karen Patterson, Sharavi Gandham, Kailazarid Gomez, Barbra Richardson, and the MTN-001 Study Group

Questions: Informing RCTs

   Acceptability  Do women prefer oral tablets or vaginal gel?

Adherence  Do oral and vaginal dosing have different levels of adherence?

Pharmacokinetics   Do active site drug concentrations vary with dosing form?

Is there an additive effect of dosing oral tablet and vaginal gel together?

   

Study Design

Three period, open label crossover study 144 sexually active, HIV- women, 18-45 y.o., 7 sites All receive oral, vaginal, dual – random sequence    Daily oral tenofovir disoproxil fumarate (TDF, 300 mg tablet) Daily vaginal tenofovir gel (1% TFV, 40 mg; same as VOICE) Daily oral and vaginal (Dual) 21 weeks (3, 6-week periods; 1 week washout) Screen Regimen A w/o Regimen B w/o Regimen C Exit WK -4  0 3

6

7 10

13

14 17

20

Safety, adherence, acceptability, PK @ each visit 21

Adverse Events*

     No differences in overall AEs among regimens Nausea, diarrhea, headache more common with oral & dual dosing (all <15%) Genital symptoms not different by regimen  Vaginal 21%, Dual 21%, Oral 18% Hypophosphatemia – most common lab AE, transient  Vaginal 11%, Dual 15%, Oral 15% 17 Grade 3 or 4 AEs   9 hypophosphatemia (4 oral, 2 vaginal, 3 dual) Migraine (only Gr. 4), hives, malaria, procedure, weight loss (2), anemia (2) *Based on 168 randomized participants, not only 144 evaluable.

200 100 0 500 400 300

Serum TFV & PBMC TFV-DP

Serum TFV (median, IQR) PBMC TFV-DP (median, IQR) Dual Oral Vaginal 60 50 40 30 20 10 0 Dual Oral Vaginal 0 2 4 Hours 6 8 10 0 2 4 Hours 6 8 All anatomic sites, except serum, lacked temporal trends over 8 hrs.

10

TFV & TFV-DP by Route & Site

8 7 6 5 4 3 2 1 0 -1 %BLQ -2 0 0 0 * 0 0 71 * 1 56 4 * 3 52 3 * 2 34 5 * 1 42 3     Route Dual Oral Vaginal Vaginal dosing achieves active drug (TFV-DP) concentrations in tissue >100x higher than with oral dosing No additive effect of Dual TFV-DP ~5-15% of TFV in the same compartment Effective concentrations have not been established *Median

Rectal Sponge Tenofovir

279 198 19 19,201 662 4,361 Median N Dual Oral Vaginal Friedman p=0.01 comparing among regimens; Dual vs. Oral p=0.01 (Wilcoxon), o/w n.s.

*Numbers are unadjusted for weight.

Self-Reported Product Adherence

Overall N=851‡ % Vaginal Gel N=285 % Oral Tablets N=282 % Dual N=284 %

Adherence Measures

% daily doses taken (mean, SD)† >=90% doses taken 94.0 (10.8) 94.4 (12.2) 93.9 (10.1) 93.8 (10.2) 81 85 79 79 †p=0.8 (mixed effect model with Gaussian link and fixed effects for treatment, period, sequence; random effect of participant within sequence).

‡N=visits among 144 participants; maximum of 864 possible visits.

No differences in among regimens or across study sites.

PK as Adherence Measure

Vaginal Dose Phase Oral/Dual Dose Phase

Mean Lower 95%CI Upper 95%CI Upper 99%CI C 24 L99%CI Oral Pre-Dose Dual Pre-Dose Lower 95% CI Upper 95% CI Upper 99% CI C 24

Expected

(Witnessed Dose Cohort)

Actual

(unobserved MTN-001) 64% < 99%CI 35% < 99%CI 64% < 99%CI 36% < 99%CI Reference Cohorts: JHU (ICTR, 14 C-TFV), MTN-006, CONRAD Gel Study (Jill Schwartz)

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Acceptability

Likely future use, if effective:  93% oral tablet; 83% gel (p=0.002)  Difference driven by lower, different US rates Preferences differed by location Vaginal Gel Oral Tablets Both liked equally Both disliked

Overall (%)

28 57 10 5

Africa (%)

42 40 14 3

US (%)

14 72 7 7  Many African women said that the gel improved sexual pleasure (Qualitative interviews)

Summary

    Active drug concentrations (TFV-DP) in vaginal tissue >100 times higher with gel, but “enough” for prevention is yet to be defined Dosing oral and vaginal forms together does not increase tissue concentrations more than gel alone US women prefer tablet; African women have equal preference & high likelihood of use for both products TFV concentrations indicate poor adherence in contrast to self-report, but no difference noted between regimens

Acknowledgements

  Research Participants Study Site staff  MRC, Botha’s Hill, Durban  Bronx-Lebanon, NYC      CWRU, Cleveland MU-JHU, Kampala U Pitt. CRS, Pittsburgh UAB, Birmingham MRC, Umkomas, Durban        NIH/DAIDS FHI SCHARP MTN Network Lab Clinical Pharmacology Analytical Lab (JHU) CONRAD Gilead 

MTN is funded by NIAID (5U01AI068633), NICHD, NIMH, all of the U.S. National Institutes of Health

Questions?