Paper # 35LB
MTN-001: A Phase 2 Cross-over Study of Daily Oral and Vaginal TFV in Healthy, Sexually Active Women Results in Significantly Different Product Acceptability and Vaginal Tissue Drug Concentrations
Craig Hendrix*1, A Minnis2, V Guddera3, S Riddler4, R Salata5, C Nakabiito6, C Hoesley7, J Justman8, L Soto-Torres9, B Richardson10, and MTN-001 Study Team
1Johns Hopkins Univ, Baltimore, MD, US; 2RTI Intl, Research Triangle Park, NC, US; 3MRC, Durban, South Africa; 4Univ of Pittsburgh, PA, US; 5Case Western Reserve Univ, Cleveland, OH, US; 6Makerere Univ-Johns Hopkins Univ Res Collaboration, Kampala, Uganda; 7Univ of Alabama at Birmingham, US; 8Columbia Univ, New York, NY, US; 9NIH, Bethesda, MD, US; and 10Univ of Washington, Seattle, US
Background: Oral and vaginal preparations of
tenofovir (TFV) reduce the risk of HIV infection in select populations. Adherence
to regimen and active site TFV concentrations are interrelated and ultimately
inform an understanding of TFV’s efficacy.
Methods: We completed a phase 2, open label,
3-period cross-over study in sexually active HIV uninfected women at 4 US and 3 African sites. In each period, subjects received a randomized sequence of 300 mg
oral TFV disoproxil fumarate (OT), 40 mg vaginal TFV gel (VT), or both
formulations (DT) daily for 6 weeks. Safety, adherence, acceptability, and drug
concentration were monitored during each period.
Results: A total of 144 women completed 98.5% of
scheduled visits. All 3 regimens were well tolerated. Nausea occurred more
frequently with OT (15%) and DT (14%) than VT (3%). Mean self-reported drug
adherence was 94% and did not differ across formulations (p = 0.8).
Subjects reported they would be likely to take study product in the future as
follows: OT 93%, VT 83%, DT 82%. The preference for oral product was
statistically significant comparing OT to VT (p = 0.002) and largely
driven by US sites. Women at the African sites cited the gel’s effect on sexual
pleasure as a positive attribute. Median drug concentrations are in the Table.
OT and VT serum and peripheral blood mononuclear cell (PBMC) concentrations of
TFV and TFV diphosphate (TFV-DP) were consistent with prior healthy volunteer
studies. Tissue TFV-DP was below limits of quantitation in 5%, 6%, and 83% of DT,
VT, and OT subjects, respectively.
|
Site and Drug Measured (Units)
|
OT
|
VT
|
Paired OT:VT Ratio
|
|
Serum TFV Peak (ng/mL)
|
332
|
3.7
|
74
|
|
PBMC TFV-DP Peak (fmol/106 cells)
|
52
|
1.6
|
54
|
|
Vaginal Tissue TFV (ng/mg)
|
0.2
|
113
|
0.001
|
|
Vaginal Tissue TFV-DP (fmol/mg)
|
22
|
2351
|
0.01
|
|
Endocervical Cytobrush TFV-DP (fmol/106 cells)
|
72
|
1078
|
0.05
|
|
Cervicovaginal Lavage TFV (ng/mL)
|
0.01x106
|
6.7x106
|
0.001
|
Conclusions: All 3 study regimens were well
tolerated and acceptable. Self-reported adherence was very high (94%) and US subjects preferred oral product. Tissue TFV-DP, the active drug form, was 2 log10
higher after vaginal dosing than oral dosing, raising concern about the
relative efficacy of oral dosing to prevent vaginal transmission. Efficacy,
however, also depends on unknown TFV-DP concentration-response relationships.
The relevance of these results for predicting TFV’s preventive efficacy in men
or women depends both on rates of vaginal vs. anal sex and on TFV-DP
differences between the vagina and rectum.
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