CONSORT flowchart.

<p>CONSORT flowchart.</p

Study flow diagram.

<p>Paired measures from compartment concentrations (CC) and both CC and biopsy samples (*) taken at the bolded visits: V3 (Visit 3: ∼30 mins post single oral dose), V5 (1–6 days post V3 dose), V6 (7–9 days post V3 dose), V7 (∼30 mins post single topical dose), V9 (1–3 days post V7 dose), V10 (7–12 days post V7 does) and V12 (∼30 mins post 7^th daily dose) used in the dose-response analysis.</p

Noncompartmental Pharmacokinetic Parameters (^*Insufficient data to perform NCA on CD4- and CD4+ PBMC; see companion publication Richardson-Harmon et.al for exposure-response analysis; ^**Composite Profile).

<p>*Insufficient data to perform NCA on CD4- and CD4+ PBMC; see companion publication Richardson-Harmon et.al for exposure-response analysis.</p><p>**Composite Profile.</p><p>Noncompartmental Pharmacokinetic Parameters (^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106196#nt101" target="_blank">*</a>}Insufficient data to perform NCA on CD4- and CD4+ PBMC; see companion publication Richardson-Harmon et.al for exposure-response analysis; ^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106196#nt102" target="_blank">**</a>}Composite Profile).</p

Demographics.

<p>Demographics.</p

TFV (A) and TFVdp (B) concentrations in rectal tissue homogenate are predicted by Rectal Sponge TFV.

<p>(p<0.001, robust RSE_TFV  = 0.67, RSE_TFVdp  = 0.66) Shaded regions are the 10–90% confidence intervals of the mean predictions from robust linear regression model. The correlations are consistent regardless of administration route and number of doses.</p

TFVdp in rectal tissue homogenate is predictive of intracellular TFVdp concentration in isolated rectal mucosal mononuclear cells (MMCs), with higher levels of phosphorylation in the CD4+ T cells compared to CD4- T cells.

<p>Intracellular TFVdp concentration in isolated rectal mucosal mononuclear cells increases linearly as TFVdp concentration in rectal tissue homogenate increases. (p<0.001, robust RSE  = 0.46) There is higher phosphorylation of TFV in CD4+ cells, seen in its higher y-intercept. The lines are the mean rectal tissue MMC TFVdp concentration predictions from robust linear regression model; solid is CD4+, dashed is CD4-. Shaded regions are the 10–90% confidence intervals of the mean prediction.</p

TFV Plasma Half-life is shorter (p = 0.02) during rectal administration.

<p>Plasma concentration-time profile is shown (median and interquartile range). Nominal time for single rectal dose was shifted right by 0.250 h and multiple rectal dose by 0.500 h for clarity. N = 18 for oral dose, 12 single rectal dose, 12 multiple rectal dose. (BLQ values are imputed as 0.01.)</p

TFV quantification from rectal sponges is predictive of plasma TFV exposure during rectal dosing.

<p>Plasma TFV exposure is correlated linearly with rectal sponge TFV exposure. (p<0.001, robust RSE  = 0.38) The linear correlation is the same regardless of number of rectal doses. Shaded regions are the 10–90% confidence intervals of the mean predictions from robust linear regression model.</p

Compartment TFV and TFVdp efficacy concentrations (EC_50,90,95) predicted by logistic regression to suppress HIV infection following single oral TDF, single topical TFV 1% gel and 7-day topical TFV 1% gel <i>in vivo</i> product use.

§<p>Predicted compartment dose concentrations to suppress 50, 90 and 95% of HIV infection interpolated from the logistic regression probability curve where infection was defined as cumulative p24 pg/mL ≥500.</p><p>Actual drug concentrations in the delivered product were 300 mg tenofovir disoproxil fumarate in the oral pill (equivalent to 245 mg of tenofovir disoproxil) and 40 mg/4 mL tenofovir in each topical gel application.</p><p>Compartment TFV and TFVdp efficacy concentrations (EC_50,90,95) predicted by logistic regression to suppress HIV infection following single oral TDF, single topical TFV 1% gel and 7-day topical TFV 1% gel <i>in vivo</i> product use.</p

Study Design.

<p>Study Design.</p