学会抄録

<p><b>Pod-IVR Pharmacokinetics in macaques</b> (A) <i>In vivo</i> release of TDF and FTC from each pod-IVR (N = 6/time point) over the course of the efficacy study determined by residual drug measurements from the pod-IVRs that were in place for 19 weeks with IVRs exchanged for new devices every 2 weeks. The top and bottom of the boxes show the 75th and 25th percentiles, respectively, and the line in the middle of the box is the median value. The dotted lines show the mean (N = 6) <i>in vivo</i> release from identical pod-IVRs obtained during the PK study preceding this efficacy study [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157061#pone.0157061.ref026" target="_blank">26</a>]. (B) <i>In vivo</i> release profile for individual macaques (T1-T6) shows variability between animals. (C) TDF, TFV, TDF+TFV, and FTC levels in vaginal fluids collected at each ring exchange. Vaginal fluids were collected with Weck-Cel sponges proximal and distal to the pod-IVR placement. The dotted horizontal lines correspond to the medians from our previous PK study [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157061#pone.0157061.ref026" target="_blank">26</a>]. Left panels-proximal; Right panels-distal; Dots-median.</p

<i>In vitro</i> evaluation of adherence IVR.

<p>Response of adherence IVR over 100 h using a simulated insertion/removal cycle of 2.5 h in and 0.5 h out (lower plot) using a programmed temperature test apparatus. Data represent the IN/OUT status (0 or 1) logged at a 5 min interval. The upper plot shows expansion of data at 6, 48, and, 96 h for three adherence IVRs measuring simultaneously. Vertical dotted lines indicate transition to “IN” temperature for each cycle shown. The temporal alignment of “IN” measurements does not vary between the three devices over 96 h of measurement. The time required for the device to respond to a simulated insertion or removal event was determined using the temperature-time data shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0174729#pone.0174729.g005" target="_blank">Fig 5</a>. The device was exposed to three repeated step changes in temperature between 28°C and 37°C, and response was calculated as the time required for the device to measure the range of 10% to 90% of the total 9°C temperature change (28.9°C and 36.1°C). For the step from 28°C to 37°C (simulated insertion), the 10%-90% time was 1.84 ± 0.006 min. For the step from 37°C to 28°C (simulated removal), the 90% to 10% time was 1.96 ± 0.096 min.</p

Electronics module design and function.

<p>(a) Diagram of adherence IVR electronics module showing major functional components (boxes) and dataflow (arrows). (b) Plot showing relationships between reference temperature, comparator reference voltage (V_ref), and the 4-bit V_ref generator parameter. Each point represents a reference temperature that is set in software by the generator 4-bit value (0–15). Here a generator value of 11 is set to select a reference temperature of 34°C. Dotted lines indicate V_ref values selected for IN/OUT determination and “Logging On” “Logging Off” functionality in the <i>in vitro</i> and <i>in vivo</i> testing of adherence IVR devices.</p

<i>In vivo</i> sheep study events timeline.

<p><i>In vivo</i> sheep study events timeline.</p

Adherence-monitoring IVR prototype.

<p>(a) Adherence IVR prototype with electronics module embedded in IVR elastomer circumference as used in <i>in vitro</i> simulation experiments. For clarity, the IVR is shown prior to sealing the circuit board and cylindrical battery pack in place using silicone adhesive. (b) Close-up of prototype electronics module. (c) Cutaway 3D model of adherence IVR prototype used in sheep study. The electronics module and battery are enclosed in a central compartment rather than sealed in the IVR circumference to allow access to the electronics during initial <i>in vivo</i> evaluation. A portion of the central compartment wall is removed in the drawing to expose the electronics module and battery.</p

Adherence IVR temperature response analysis.

<p>(a) Temperature measured by the thermistor as a function of time during three cycles of alternating between two controlled temperature chambers maintained at 28°C and 37°C, respectively. (b) Zoomed data for first cycle showing individual temperature readings collected at 10 s intervals. The lower and upper gray dotted lines indicate the values at 10% and 90%, respectively, of the full-scale measured temperature change.</p

<i>In Vivo</i> Evaluation of Adherence IVR.

<p>Device response as a function of time for a series of insertion and removal periods in a sheep vaginal model. The black trace is the logged data (1 min logging interval) retrieved from the device at the study conclusion. The actual time for removal and insertion events is indicated by the symbols above the black trace. The gray trace shows the temperature as a function of time for the three ring dispositions: water bath (50°C) sheep vaginal temperature measured at the start of the study (39°C), and ambient laboratory temperature (25°C).</p

Prevention of vaginal and rectal HIV transmission by antiretroviral combinations in humanized mice

<div><p>With more than 7,000 new HIV infections daily worldwide, there is an urgent need for non-vaccine biomedical prevention (nBP) strategies that are safe, effective, and acceptable. Clinical trials have demonstrated that pre-exposure prophylaxis (PrEP) with antiretrovirals (ARVs) can be effective at preventing HIV infection. In contrast, other trials using the same ARVs failed to show consistent efficacy. Topical (vaginal and rectal) dosing is a promising regimen for HIV PrEP as it leads to low systematic drug exposure. A series of titration studies were carried out in bone marrow/liver/thymus (BLT) mice aimed at determining the adequate drug concentrations applied vaginally or rectally that offer protection against rectal or vaginal HIV challenge. The dose-response relationship of these agents was measured and showed that topical tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) can offer 100% protection against rectal or vaginal HIV challenges. From the challenge data, EC₅₀ values of 4.6 μM for TDF and 0.6 μM for FTC for HIV vaginal administration and 6.1 μM TDF and 0.18 μM for FTC for rectal administration were obtained. These findings suggest that the BLT mouse model is highly suitable for studying the dose-response relationship in single and combination ARV studies of vaginal or rectal HIV exposure. Application of this sensitive HIV infection model to more complex binary and ternary ARV combinations, particularly where agents have different mechanisms of action, should allow selection of optimal ARV combinations to be advanced into pre-clinical and clinical development as nBP products.</p></div

Results of TDF + FTC combination (Round 3) dose ranging infection study.

<p>Results of TDF + FTC combination (Round 3) dose ranging infection study.</p

Results of narrow-range (Round 2) dose ranging infection study for EC₅₀ determination.

<p>Results of narrow-range (Round 2) dose ranging infection study for EC₅₀ determination.</p