CONSORT flowchart.

<p>CONSORT flowchart.</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 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

Previously unreported <i>CKM</i> missense variants detected in clinical trial participants located in Bangkok, Thailand, Cape Town, South Africa, and New York City, USA.

<p>Previously unreported <i>CKM</i> missense variants detected in clinical trial participants located in Bangkok, Thailand, Cape Town, South Africa, and New York City, USA.</p

Naturally occurring genetic variants of AK2 and the resulting impact on TFV phosphorylation.

<p>Wild-type (WT) AK2 and variants were expressed in and purified from <i>E</i>. <i>coli</i> in order to evaluate their effects on TFV phosphorylation in vitro. Proteins were incubated with 1 mM TFV in assay buffer for 2.5 h before reaction was quenched. A saturating concentration of TFV was used in order to ensure that substrate depletion would not play a causal role in differences observed in the formation of phosphates in these activity assays. TFV-MP and TFV-DP were detected by uHPLC-MS/MS where signal to noise ratio was used to establish the corresponding bar graph. Error bars represent standard deviation; n = 3. A two-tailed unpaired <i>t</i> test and significance was set as follows: *, p≤0.05; **, p≤0.01; ***, p≤0.001.</p

HPTN 067 participant enrollment location and gender information.

<p>HPTN 067 participant enrollment location and gender information.</p

Previously unreported <i>AK2</i> missense variants detected in clinical trial participants located in Bangkok, Thailand, Cape Town, South Africa, and New York City, USA.

<p>Previously unreported <i>AK2</i> missense variants detected in clinical trial participants located in Bangkok, Thailand, Cape Town, South Africa, and New York City, USA.</p

Previously unreported <i>PKLR</i> missense variants detected in clinical trial participants located in Thailand, South Africa, and the USA.

<p>Previously unreported <i>PKLR</i> missense variants detected in clinical trial participants located in Thailand, South Africa, and the USA.</p

Distribution of individuals enrolled at the Bangkok, Cape Town, and New York City study sites carrying genetic variants in TFV-activating kinases.

<p>Each rectangle is representative of a TFV-activating kinase that was sequenced: <i>AK2</i> in blue, <i>CKM</i> in pink, <i>PKM</i> in orange and <i>PKLR</i> in green. Numerical values indicate the number of individuals detected to carry a single nucleotide variation or deletion. Overlapping regions of each rectangle indicate the number of individuals with genetic variants in more than one kinase.</p