CROI 2016 Abstract eBook

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Poster Abstracts

449 PK of FTC, TFV and 3TC in Ugandan and Nigerian Breastfeeding Mother-Infant Pairs Catriona J. Waitt 1 ; Adeniyi Olagunju 1 ; Shadia Nakalema 2 ; Isabella Kyohaire 2 ; Andrew Owen 1 ; Mohammed Lamorde 2 ; Saye Khoo 1 1 Univ of Liverpool, Liverpool, UK; 2 Infectious Diseases Inst, Makerere Univ, Kampala, Uganda

Background: Under WHO Options B and B+, increasing numbers of HIV-positive women receive antiretroviral therapy (ART) during breastfeeding. The pharmacokinetics (PK) of nucleoside reverse transcriptase inhibitors (NRTIs) to breastfed infants are incompletely understood. We present intensive PK profiles of emtricitabine (FTC), tenofovir (TFV) and lamivudine (3TC) in maternal plasma (MP), breast milk (BM) and infant plasma (IP) from Ugandan and Nigerian cohorts. Methods: Breastfeeding mothers receiving a once-daily efavirenz or nevirapine-based ART regimen were enrolled, together with their exclusively breastfed infants. Paired dried blood spots (DBS; maternal and infant) and dried breast milk spots (DMS) were collected pre-dose and serially up to 12 h post-dose. All three NRTIs were quantified using a validated simultaneous LC-MS/MS assay. Non-compartmental PK analysis was performed using WinNonLin and milk-to-plasma (M:P) ratios were calculated arithmetically. Results: 21 Ugandan and 27 Nigerian mother-infant pairs were enrolled. Populations were similar for mean maternal age (30 years) and weight (60 Kg), and infant age (100 days) and weight (6 Kg). T max of FTC was 4 h in MP and 5.1 h in BM, reaching median C max of 493 (IQR 467-627) and 933 (716-1238) ng/mL, respectively. The AUC 0-12 of FTC was 2492 (511-3260) and 4134 (824-7286) ng.h/mL in MP and BM, with a M:P AUC ratio of 2.13 (SD 1.77). FTC was detected in 18.7% of exposed infants with a median concentration of 18.5 (SD 3.4) ng/mL. TFV had a T max of 1 h in MP and 4 h in BM, reaching C max of 186 (109-240) and 7.3 (5.5-9.6) ng/mL in these compartments, respectively. The AUC 0-12 was 1014 (738-1394) and 41.5 (23.2-56.1) ng.h/mL in MP and BM, giving a M:P AUC ratio of 0.034 (SD 0.09). No infant had measurable TFV. 3TC had a C max of 991 (574-1129) ng/mL in MP and 572 (386-710) ng/mL in BM. The AUC 0-12 of 3TC in MP and BM was 3916 (2985-6780) and 4001 (1951-4577) ng.h/mL, respectively, with a M:P AUC ratio of 1.02 (SD 0.79). 3TC was detectable in 41% of exposed infants with a median concentration 16.4 (SD 8.5) ng/mL. Conclusions: This is the first report of full PK profiles of FTC and TFV in plasma and BM of breastfeeding mother-infant pairs, indicating higher concentration of FTC in BM compared to MP but transfer to IP only in a minority. TFV is measurable in BM but is not detectable in IP. Consistent with previous studies, 3TC levels in BM were comparable to MP with transfer to IP in almost half the infants.

450 Multispecies Differences in Drug Transporter Expression and Localization in GI Tissue Corbin Thompson 1 ; Elias P. Rosen 1 ; Paige Charlins 2 ; Leila Remling-Mulder 2 ; Martina Kovarova 1 ;Yuri Fedoriw 1 ; Paul Luciw 3 ; J.Victor Garcia 1 ; Ramesh Akkina 2 ; Angela Kashuba 1 1 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 2 Colorado State Univ, Fort Collins, CO, USA; 3 Univ of California Davis, Davis, CA, USA Background: HIV replication may persist during treatment within tissue reservoirs, including the gastrointestinal (GI) tract. Differences in drug transporter expression and localization may alter ARV exposure and confound the ability to translate study results between animal models, and to humans. Here, we characterize the expression and localization of transporters relevant to ARVs in 3 animal models. Methods: Three cohorts of uninfected animals (rhesus macaques (NHP, n=3); humanized mice (BLT, n=6 and hu-HSC-Rag, n=18)) were dosed to steady-state with a combination of ARVs including tenofovir (TFV), emtricitabine (FTC), and raltegravir (RAL). Ileum and rectumwere collected at necropsy and analyzed for gene (qPCR) and protein (Western blot) expression and localization (immunohistochemistry (IHC)) of ARV efflux (ABCB1, ABCG2, ABCC1, ABCC2, and ABCC4) and uptake (SLC29A1, SLCO2A1, SLC22A3) transporters. Tissue concentrations were analyzed by LC-MS and normalized to plasma. Species comparisons were performed using ANOVA. Data are reported as mean fold expression vs GAPDH. Results: In the ileum, gene expression differed significantly between BLT and hu-HSC-Rag mice for ABCB1 (5.02 vs 23.4 x 10 -4 ;p=0.005), ABCC2 (0.11 vs 0.19;p=0.01), and ABCC4 (4.56 vs 1.91 x 10 -6 ;p=0.005). Protein expression did not differ between these 2 models (p>0.05). Iliac NHP gene expression was increased over mouse for ABCB1 & ABCC4 (1.7 & 3.3 log;p<0.01) and decreased for SLC22A3 (3.2 log;p<0.01). In the colorectum, gene differences were again observed between BLT and hu-HSC-Rag mice for ABCB1 (2.08 vs 26.3 x 10 - 4 ;p<0.001), SLC29A1 (0.07 vs 0.04;p=0.019), and ABCG2 (0.11 vs 0.05;p=0.001). No interspecies differences were seen. In all species, IHC showed MDR1 localization on the luminal surface of ileac and rectal mucosa and a lack of MRP2 expression. hu-HSC-Rag TFV tissue concentrations were 13 & 8-fold greater than BLTs and NHPs (p<0.05). Conclusions: This is the first study comparing the expression and localization of these transporters across animal models. Observed variability in expression suggests model- dependent ARV tissue penetration (e.g. decreased ABCB1 and increased ABCC4 expression in BLT mice explain the observed decrease in TFV exposure). Multi-log increases in ABCB1 expression between NHP and mice may impact the disposition of many ARVs that use ABCB1 for transport (e.g. TFV and RAL). Ultimately, these data can be coupled with ARV exposure data to inform inter-species drug scaling for targeting HIV reservoirs. 451 Antiretroviral Use and Implications for DAA Therapy in HIV/HCV Coinfection Marianne Martinello 1 ; Gregory J. Dore 1 ; Jasmine Skurowski 1 ; Rohan I. Bopage 2 ; Robert Finlayson 3 ; David Baker 4 ; Mark Bloch 5 ; GailV. Matthews 1 1 Kirby Inst, Univ of New South Wales, Sydney, Australia; 2 The Albion Cntr, Sydney, Australia; 3 Taylor Square Private Clinic, Sydney, Australia; 4 East Sydney Doctors, Sydney, Australia; 5 Holdsworth House Med Practice, Sydney, Australia Background: Interferon-free directly-acting antiviral (DAA) regimens for HCV provide a major advance in clinical management, including in HIV/HCV co-infection. Drug-drug interactions (DDI) with combination antiretroviral therapy (cART) will require consideration. The aim of this analysis was to characterise the cART regimens in HIV/HCV co-infected individuals and their suitability for co-administration with the following DAA HCV regimens: sofosbuvir/ledipasvir, paritaprevir/ritonavir/ombitasvir and dasabuvir, grazoprevir/ elbasvir and sofosbuvir plus daclatasvir. Methods: CEASE-D is a prospective cohort of HIV/HCV co-infected individuals in Sydney, Australia. This analysis included all individuals enrolled between July 2014 and August 2015 (n=191). The primary endpoint was the proportion of individuals receiving suitable cART for co-administration with approved or investigational (Phase III) interferon-free DAA regimens.

Poster Abstracts

173

CROI 2016