CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

535 Imaging the Spatial Distribution of Efavirenz in Intact HIV Tissue Reservoirs Elias P. Rosen 1 ; Corbin G.Thompson 2 ; MarkT. Bokhart 1 ; Craig Sykes 2 ;Yuri Fedoriw 2 ; Paul Luciw 3 ; David C. Muddiman 1 ; Angela D.M. Kashuba 2 1 North Carolina State University, Raleigh, NC, US; 2 University of North Carolina, Chapel Hill, NC, US; 3 University of California Davis, Davis, CA, US Background: Methods to accurately evaluate ARV biodistribution within tissues are needed to design effective HIV therapy and eradication strategies. Here, we characterize the spatial distribution of efavirenz (EFV) within suspected reservoir tissues of a primate model using a novel approach to mass spectrometry imaging (MSI). Methods: Reservoir tissues (GALT, lymph nodes, brain, testes) were removed at necropsy from an uninfected rhesus macaque dosed orally to steady-state with EFV. 10 μ m cryosections of snap frozen tissue were discretized into 10 -4 mm 3 voxels, resolving 100 μ m features, and analyzed using an infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) source coupled to a Thermo Q-Exactive mass spectrometer. Response was calibrated by EFV standards on blank tissue, with a limit of detection of 180 attomole/voxel (57 fg/mm 3 tissue). The results were visualized using custom analysis software. Serial sections of tissue were utilized to validate MSI results by LC-MS, and stained to correlate observed EFV response with tissue morphology (H&E) and immunohistochemistry (CD3 staining). Results: The presence of EFV was confirmed in all reservoir tissues by MSI, with varying total EFV penetration observed between tissue types. Mapping of EFV response indicated heterogeneous drug exposure. EFV concentration was substantially increased within the mucosa and lamina propria of the colorectal epithelium, specifically corresponding to high density of CD3+ T cells. No such mucosal enhancement was observed in the ileum. Lymph nodes showed focally increased signal in association with some, but not all, primary follicles. Within the brain, grey matter had enhanced EFV exposure relative to white matter. EFV concentration was lowest (167 pg/g tissue) in the basal ganglia, increasing to approximately two-fold in most other tissues (cerebrum, lymph nodes, spleen, testes, and most GALT), and highest in rectal tissue (3.6 fold).

Conclusions: This study is the first to map the biodistribution of an ARV in viral reservoir tissues. Differences in mucosal enhancement in the gut suggest potential differences in biologic transporter activity. Heterogeneous lymph node distribution may indicate insufficient exposure at important sites of viral replication. By differentiating and quantifying drug exposure between cell types within tissue, IR-MALDESI MSI offers a new capability to evaluate drug efficacy and will help inform the selection of optimal interventions to target active viral reservoirs. 724 Cancer in HIV-Infected Children: Record Linkage Study in South Africa Julia Bohlius 6 ; Nicky Maxwell 2 ; Brian Eley 3 ; Hans Prozesky 4 ; Shobna Sawry 1 ; Karl-GünterTechnau 1 ; Alan Davidson 2 ; Cristina Stefan 5 ; Matthias Egger 6 On behalf of IeDEA Southern Africa 1 University of the Witwatersrand, Johannesburg, South Africa; 2 University of Cape Town, Cape Town, South Africa; 3 Red Cross War Memorial Children’s Hospital, Cape Town, South Africa; 4 University of Stellenbosch and Tygerberg Academic Hospital, Cape Town, South Africa; 5 Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa; 6 University of Bern, Bern, Switzerland Background: The incidence of AIDS- and non AIDS-defining cancers in HIV-infected children and the impact of ART has not been evaluated in sub-Saharan Africa. We examined the incidence of cancer in HIV-infected children enrolled in antiretroviral therapy (ART) programmes in South Africa, using record linkage techniques. Methods: We linked records of patients aged ≤ 16 years from five ART programmes (Harriet Shezi and Rahima Moosa in Johannesburg; Khayelitsha, Red Cross and Tygerberg in Cape Town) to the records of the four corresponding paediatric oncology units (Baragwanath and Charlotte Maxeke in Johannesburg; Red Cross and Tygerberg in Cape Town). Records were linked based on folder numbers, names, birth date and sex. Missing CD4 cell counts and percentages were multiply imputed. We calculated incidence rates and hazard ratios (HR) from Cox regression models including ART, sex, age, and immunodeficiency. Results: Data of 11,707 HIV-infected children (29,348 person-years [pys]) were included in the analysis. Median age at enrolment was 6 years in children developing and 2.5 years in children not developing cancer. We identified 24 incident cancer cases, for an incidence rate of 82/100,000 pys (95% CI 55-122). Kaposi Sarcoma and Non Hodgkin Lymphoma were the most frequent cancers with incidence rates of 34 and 31/100,000 pys, respectively. There were few non AIDS-defining malignancies. In multivariate analysis, children on ART had a lower risk of developing cancer compared to children not on ART. The risk of developing cancer increased with age and more advanced immunodeficiency (Table). In

Oral Abstracts

children with cancer, one year survival was 73% (95% CI 61-82%). Risk of developing cancer among HIV-infected children in South Africa

HR: hazard ratio, ART: antiretroviral therapy; CI: confidence interval

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CROI 2015