CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Of the product discontinuations, 6 (8%) LA and 2 (5%) P were due to AEs including one P arm participant with prolonged QTc interval. Transient Gr ≥2 liver abnormalities occurred in 9 (11%) of the LA participants compared with 4 (10%) in the P arm. Three LA arm participants developed Gr ≥3 injection site reactions compared with none in the P arm. No significant difference was observed between the two arms. Among participants who received ≥ one injection, the median trough concentration (CTrough) of RPV was 68.2 ng/ mL. At Week 52 (eight weeks after last injection), the CTrough was 91.9 ng/mL. The concentration two weeks (C2WK) after the first and second injections (at Weeks 6 and 14) was 85.5 ng/mL and 113 ng/mL, respectively. At the last injection visit, 61% of women strongly agreed that they would definitely use and 73% that they would think about using a PrEP injectable in the future. Conclusion: TMC278 LA IM injections administered every eight weeks in this clinical trial cohort of African and US women were safe, overall well tolerated and acceptable. The lower quartile RPV concentrations were consistently above the PA-IC90 at all times through eight weeks post injection. 422LB TRANSCUTANEOUS REFILLABLE NANOFLUIDIC IMPLANT FOR CONSTANT DELIVERY OF HIV PREP Corrine Xuan Chua 1 , Priya Jain 1 , Ming Hu 2 , Peter L. Anderson 3 , Jason T. Kimata 4 , Jagannadha Sastry 5 , Roberto Arduino 5 , Alessandro Grattoni 1 1 Houston Methodist Rsr Inst, Houston, TX, USA, 2 Univ of Houston, Houston, TX, USA, 3 Univ of Colorado Denver, Aurora, CO, USA, 4 Baylor Coll of Med, Houston, TX, USA, 5 Univ of Texas, Houston, TX, USA Background: Antiretroviral drugs such tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), are effective as HIV preventive, pre-exposure prophylaxis (PrEP). Unfortunately, poor patient adherence has rendered treatment less effective. TDF success motivated development of tenofovir alafenamide (TAF), which is more potent with reduced side effects. However, patient adherence remains a concern. To address this, we developed a novel transcutaneously refillable nanochannel system (nDS) for the delivery of TAF and FTC for HIV PrEP. We hypothesized that the nDS implant could deliver sustained doses of TAF and FTC as PrEP to prevent infection from SHIV challenge in non-human primates long term. Methods: We microfabricated silicon nanochannel membrane with channels as small as 2.5 nm in compliance with FDA requirement for implantable devices. nDS implants achieved constant release therapeutics in small and large animal models for over 6 months. In this study, nDS was tailored for the controlled delivery of TAF and FTC (received in kind from Gilead). Ti implants were designed for transcutaneous refilling to extend the duration of treatment. Implants loaded with TAF and FTC were tested in vitro for 3 months to assess release rates and drug stability. PK studies were then performed in vivo in three rhesus macaques with implants subcutaneously inserted in the dorsum and transcutaneous refilling tested at day 70. Plasma and biopsy samples were collected at different timepoints and TFVpp and FTCtp concentration quantified in PBMCs. Results: The implant demonstrated sustained release of both TAF and FTC for over 83 days. Both TAF and FTC maintained bioactivity over the duration of the study. PK data (figure 1) showed that nDS achieved sustained preventative levels of TFVpp above 70 fmol/million PBMCs over 83 days. For FTCtp levels of approximately 1.5 pmol/million PBMCs were sustained for 28 days followed by a decrease in PBMC levels due to a decline of FTC in the implant reservoir. Transcutaneous refilling proved successful with FTCtp levels again reaching above 1.5 pmol/million PBMCs. Implants were well tolerated by the animals and surrounding tissues. Conclusion: nDS achieved sustained delivery of TAF and FTC at approximately 2 and 100 mg/day, respectively, compatible with HIV PrEP. Successful transcutaneous refilling was achieved. Current studies supported by NIH and Gilead are examining the potential of nDS as a breakthrough delivery system addressing the current limitation of HIV PrEP.

Poster and Themed Discussion Abstracts

423 AN IN VITRO–IN SILICO STUDY OF REDUCED-DOSE EFAVIRENZ INTERACTION WITH LEVONORGESTREL Owain Roberts 1 , Paul Curley 1 , Rajith Kumar Reddy Rajoli 1 , Darren M. Moss 1 , Mohammed Lamorde 3 , Andrew Owen 1 , Kimberly K. Scarsi 3 , Marco Siccardi 1 1 Univ of Liverpool, Liverpool, UK, 2 Infectious Diseases Inst Ltd, Kampala, Uganda, 3 Univ of Nebraska, Omaha, NE, USA

Background: Efavirenz (EFV)-based ART remains the preferred first-line ART regimen in low- and middle-income countries and progestin-containing implants are recommended forms of hormonal contraception for HIV-infected women. However, a recent drug-drug interaction (DDI) study showed 57% lower LNG concentrations, along with unintended pregnancies, when the implant was combined with EFV 600 mg. The aim of this study was to quantify the extent of DDI between EFV and LNG using an in vitro approach, and to apply a physiologically-based pharmacokinetic (PBPK) model to simulate the effects of reduced-dose EFV on LNG pharmacokinetics (PK). Methods: Primary human hepatocytes were incubated with EFV (0.033–0.33 µM) in Williams’ E medium over 72 hours, followed by co-incubation with LNG (1 nM) for one hour. Resultant LNG concentrations were quantified using LC-MS/MS, and mean ± SD LNG apparent intrinsic clearance (CLint.app; μl/min/million hepatocytes) from two separate donors performed in triplicate was calculated. The in vitro data and published PK data were used to inform a PBPK model using MATLAB R2013b to simulate LNG plasma concentrations during co-administration of a 150 mg sub-dermal LNG implant plus 400 mg or 600 mg daily EFV in 100 individuals at 4, 12 and 24 weeks. Results: Under control conditions where cells were treated with LNG alone, LNG CLint.app was 27.1 ± 7.6 μl/min. Incubation of hepatocytes with 0.033 µM EFV increased LNG CLint.app to 39.2 ± 9.3 μl/min (+44% compared to control), whilst incubation of hepatocytes with 0.1 µM and 0.33 µM resulted in increases in LNG CLint.app of 41.0 ± 7.5 μl/min and 39.2 ± 6.4 μl/min (+51% and +44% compared to control), respectively. Using a PBPK model, LNG PK was calculated at 4, 12 and 24 weeks (Table 1). Compared to the control group, simulated LNG concentrations were 56-57% lower in patients receiving 600 mg EFV and 49-50% lower in patients receiving 400 mg EFV. Conclusion: Using concentrations spanning the therapeutic range of EFV, DDIs between EFV and LNG were quantified using an in vitro model of drug metabolism. At each concentration tested, incubation with EFV significantly increased LNG CLint.app. PBPK simulations found that reducing the EFV dose from 600 mg to 400 mg only modestly decreased the magnitude of the EFV-LNG DDI; therefore, reduced-dose EFV may not mitigate the risk of contraceptive failure when combined with standard dose LNG. These data will be useful to aid in the optimisation of dosing strategies for combining LNG implants with ART.

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