CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

510 Pharmacokinetic and Pharmacodynamic Evaluation of NNRTI IQP-0528 DuoGel™ in Macaques Lara E. Pereira 1 ; Pedro Mesquita 2 ; Anthony Ham 3 ;Tyana Singletary 4 ; Janet McNicholl 5 ; KarenW. Buckheit 3 ; Robert Buckheit 3 ; James M. Smith 5 1 LifeSource Biomedical LLC,, Moffett Field, CA, US; 2 Albert Einstein College of Medicine, Bronx, NY, US; 3 ImQuest BioSciences,, Frederick, MD, US; 4 Anyar Inc., Fort Walton Beach, FL, US; 5 US Centers for Disease Control and Prevention (CDC), Atlanta, GA, US Background: Unprotected receptive anal intercourse (RAI) is also practiced by women, providing strong rationale for the development of an HIV microbicide gel that is suitable for both rectal and vaginal applications. This would remove the need for separate products and dosages for women who engage in RAI and vaginal intercourse, thereby helping to increase user adherence and potentially cutting costs associated with separate products. A DuoGel™ product containing 1%wt/vol IQP-0528, which has non-nucleoside reverse transcriptase and entry inhibitory activities, was developed and first evaluated vaginally in pigtailed (PM) and rhesus (RM) macaques. Methods: DuoGel™ formulation was optimized for dual compartment application. A 1.5 ml volume of 1% IQP-0528 DuoGel™ was applied vaginally to 6 SHIV+ female RM and 6 naïve female PM. Blood, vaginal pH measurements, cervicovaginal lavage, and vaginal and rectal spears were collected before, and up to 24 hours after gel application. Vaginal and rectal biopsies were also collected from PM at 24 hours. The RM were euthanized at 4 hours, and vaginal, cervical, rectal, and regional lymph node tissues were harvested for drug analysis. Anti-viral activity was tested ex vivo by co-culturing RM vaginal tissues with activated human peripheral blood mononuclear cells (PBMC), and measuring p24 levels up to 10 days after challenge with HIV-1 Ba-L . Drug levels in plasma, vaginal fluids, and tissues were determined using LC-MS. Results: In RM, median levels of IQP-0528 were between 10 4 -10 5 ng/g in vaginal and cervical tissue, and 10 5 -10 7 ng/ml in vaginal fluids for 4 hours after gel application. Bi-directional dosing was shown by median IQP-0528 levels being between 10 3 -10 4 ng/g in rectal tissues. Similar levels were observed in PM vaginal fluids for 4 hours post gel application, but IQP-0528 was not detected in the rectum. Vaginal pH remained within normal range for both species (6.5-9). Vaginal tissues obtained from RM at necropsy protected co-cultured PBMC from HIV-1 infection ex vivo , with a viral inhibition range of 90-100%. Anti-viral activity was observed in vaginal tissues that were proximal, medial, and distal relative to the cervix. Viral inhibition was not detected in baseline tissue samples. Conclusions: These data suggest that 1.5 ml of DuoGel™ delivers IQP-0528 throughout the macaque vaginal compartment at levels that are highly inhibitory to HIV-1 infection. Rectal PK studies are underway. 511 Tenofovir PK in Adults With Renal Dysfunction on LPV/r and NNRTI-Based ART Tim R. Cressey 1 ; Anchalee Avihingsanon 2 ; Guttiga Halue 3 ; Prattana Leenasirimakul 4 ; Pra-ornsuda Sukrakanchana 5 ; AnthonyT. Podany 6 ; Courtney Fletcher 6 ; Gonzague Jourdain 5 ;Virat Klinbuayaem 7 ; Chureeratana Bowonwatanuwong 8 1 PHPT-IRD UMI 174 Chiang Mai University/Harvard School of Public Health, Chiang Mai, Thailand; 2 HIV Netherlands Australia Thailand Research Collaboration, Bangkok, Thailand; 3 Phayao Hospital, Phayao, Thailand; 4 Nakornping Hospital, Chiang Mai, Thailand; 5 Chiang Mai University, Chiang Mai, Thailand; 6 University of Nebraska Medical Center, Omaha, NE, US; 7 Sanpatong Hospital, Sanpatong, Thailand; 8 Chonburi Hospital, Chonburi, Thailand Background: The recommended tenofovir disoproxil fumarate (TDF) dose is 300 mg every 48 hours for adults with moderate renal function impairment (creatinine clearance 30-49 mL/min). Coadminsitration of TDF with lopinavir/ritonavir (LPV/r) increases plasma tenofovir (TFV) concentrations in adults with normal renal function. We compared the plasma and intracellular pharmacokinetics (PK) of TDF 300 mg every 48 hours in HIV-infected adults with moderate renal function impairment receiving LPV/r and NNRTI-based antiretroviral therapy. Methods: Data were collected within a phase I, non-randomized, open-label pharmacokinetic study of TDF in patients with renal dysfunction (ClinicalTrials.gov Identifier: NCT01671982). Consenting HIV-positive adults with a confirmed creatinine clearance (CrCL) 30 to <50 mL/min receiving TDF 300 mg every 48 hours per standard of care as part of a LPV/r- or NNRTI-based ART and an HIV-1 RNA viral load (VL) <50 copies/mL were included. HBs-antigen positive adults were excluded. Intensive steady-state 48-hour blood sampling for PK assessment was performed, blood samples were collected pre-dose and then at 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 12, 24, 36, 48 hours post-dose. Peripheral blood mononuclear cells (PBMCs) were also collected at 48 hours post-dose for assessment on intracellular tenofovir di-phosphate concentrations. PK parameters were calculated using non-compartmental analysis. Results: 40 HIV-infected adults (55% female) were enrolled. Median (range) age was 56 years (39-82), weight 51 kg (38-80), serum creatinine (SCr) 1.3 mg/dL (0.8-2.1), CrCL 43.9 mL/min (30.9-49.7) and CD4 count 502 cells/mm 3 (113-1063). Tenofovir PK data were evaluable from 19 subjects receiving an NNRTI- (9 nevirapine and 10 efavirenz) and 18 receiving LPV/r-based HAART. Tenofovir plasma and intracellular PK parameters are presented in the table below: Mean tenofovir plasma AUC 0-24 was 1.7-fold higher with coadminsitration of LPV/r compared to NNRTIs.

Poster Abstracts

Tenofovir PK Parameters Conclusions: Tenofovir plasma exposure was significantly higher with LPV/r versus NNRTI based ART in patients with moderate renal function impairment. In contrast, trough intracellular TFV-diphosphate concentrations were similar between the two ART regimens. 512 Population Pharmacokinetics of CotrimoxazoleWest African HIV-Infected Children Claire Pressiat 1 ; Sihem Benaboud 2 ; Jean-MarcTreluyer 1 ;Véronique Méa-Assande 3 ; CarolineYonaba 4 ; Sophie Dattez 5 ; DiarraYe 6 ;Yi ZHENG 1 ; Valeriane Leroy 5 ; Déborah HIRT 1 MONOD ANRS 12206 1 Paris Descartes University, EA 08, Paris, France; 2 Clinical Pharmacology Department, AP-HP, Paris Centre Hospital Group, Paris, France; 3 Avocatier Health Center, Abidjan, Côte d’Ivoire; 4 Department of Paediatrics, CHU Yalgado Ouedraogo, Ouagadougou, Burkina Faso; 5 Institute of Public Health, Epidemiology and Development (ISPED), University of Bordeaux, Bordeaux, France; 6 Department of Paediatrics, CHU Charles de Gaulle, Université de Ouagadougou, Ouagadougou, Burkina Faso Background: Cotrimoxazole (association of sulfamethoxazole (SMX) and trimethoprim (TMP)) is recommended to prevent opportunistic infections in HIV-infected children. Despite the overwhelming use of this medication, few pharmacokinetics (PK) data are available in children. We investigated the PK of cotrimoxazole in a therapeutic cohort of children initiated < 2 years of age on a combination antiretroviral therapy (cART).

336

CROI 2015