CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

851 Dysregulated Epigenome in Perinatally HIV-Infected Children on ART Stephanie Shiau 1 ; Stephen M. Arpadi 1 ; Renate Strehlau 2 ; AvyViolari 2 ; ShuangWang 3 ; Faeezah Patel 2 ; Marc Foca 1 ; Ashraf Coovadia 2 ; Elaine J. Abrams 4 ; Louise Kuhn 3 ; for the CHANGES StudyTeam 1 Columbia Univ Med Cntr, New York, NY, USA; 2 Univ of the Witwatersrand, Johannesburg, South Africa; 3 Columbia Univ, New York, NY, USA; 4 ICAP, Columbia Univ Mailman Sch of PH, New York, NY, USA Background: Perinatal acquisition of HIV and early initiation of antiretroviral therapy (ART) takes place in a critical developmental period during which the epigenome may be influenced. To investigate the cumulative impact of perinatal HIV infection and ART on the epigenetic profile of school-aged children and identify affected biological pathways, we conducted an epigenome-wide association study. Methods: Genome-wide DNA methylation profiling was used to identify differentially methylated regions (DMRs) associated with HIV in 120 HIV-infected and 60 frequency age-matched HIV-uninfected children aged 4-9 years participating in an observational study at two sites (Empilweni Services and Research Unit and Perinatal HIV Research Unit) in Johannesburg, South Africa. HIV-infected children were initiated on ART ≤24 months of age, consistently on treatment (did not interrupt), and currently suppressed (HIV RNA <400 copies/mL) on a LPV/r-based regimen. DNA methylation was assayed using the Illumina Infinium HumanMethylation450 BeadChip array. Pre-processing, including filtering and beta-mixture quantile normalization, and analysis was performed with the R/Bioconductor RnBeads package. We identified significant DMRs at defined promoter regions and genes with an adjusted FDR p-value <0.05 using the limma package. Gene functional classification was explored using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The analysis was repeated stratified by sex. Results: After pre-processing and normalization a total of 424343 sites and 179 samples were suitable for analysis. Mean age was similar between HIV-infected and uninfected children (6.4 ± 1.4 vs. 6.4 ± 1.4, NS), as was the proportion of males (46.2 vs 50.0%, NS). 17067 significant DMRs at genes and 12700 at promoters were identified. Functional analysis of the top 1000 DMRs at genes identified functional clusters related to transmembrane receptors including chemokine ligands and G protein-coupled receptors, defensins, and zinc finger proteins. Among boys, 671 significant DMRs at genes and 1263 at promoters between HIV-infected and uninfected children were identified, involving similar genes. Among girls, only 1 significant DMR at a gene and 12 DMRs at promoters were identified. Conclusions: Our novel study provides evidence that perinatally acquired HIV infection may dysregulate the epigenome in school-aged children on ART. We further note that HIV may influence the epigenome differentially in boys and girls. 852 Timing of Pubertal Onset in Perinatally Infected South African Adolescents on ART Landon Myer 1 ; James Nuttall 1 ; Helena Rabie 2 ; Kirsty Brittain 1 ; Lisa Frigati 2 ; Paul Roux 3 ; Diane Gray 1 ; Linda-Gail Bekker 4 ; Heather J. Zar 1 ; for the CapeTown Adolescent Antiretroviral Cohort 1 Univ of Cape Town, Cape Town, South Africa; 2 Stellenbosch Univ, Cape Town, South Africa; 3 Groote Schuur Hosp, Cape Town, South Africa; 4 Desmond Tutu HIV Cntr, Cape Town, South Africa Background: Paediatric HIV infection is associated with delayed puberty but there are few comparative data including HIV-negative controls from southern Africa. We examined the onset of puberty in perinatally-infected adolescents in the Cape Town Adolescent Antiretroviral Cohort (CTAAC). Methods: We recruited 515 perinatally HIV-infected adolescents ages 9-14 years on ART for at least 6 months. At enrolment, individuals underwent a structured clinical interview and examination including Tanner staging and anthropometry; medical history was abstracted from routine clinical records. A comparator group of 110 age- and sex-matched HIV-negative controls underwent parallel assessments. Analyses used semi-parametric models to compare the onset of puberty (Tanner stage II or higher on genital development in males [G2] and breast and pubic hair development in females [B2 & P2, respectively]) and menarche according to age, age at ART initiation, current ART regimen, and between HIV+ and HIV- adolescents. Results: Overall 49% of HIV+ participants were female (mean age, 12.0 years; median age at ART initiation, 4.3 years; median CD4 cell count, 712 cells/uL; 76%with viral load <50 copies/mL). Comparing HIV+ participants to HIV- controls, the median weight-for-age z-score for boys was -1.14 versus -0.56 and for girls -0.71 versus 0.24. Comparing all HIV+ children to age- and sex-matched controls, the median age of pubertal onset was delayed by approximately 0.3 years in males (G2: 13.9 versus 13.6, p=0.039) and was similar among females (B2: 12.8 versus 12.9, p=0.524; P2: 13.1 versus 13.2, p=0.993). The median age of menarche was 14.2 in HIV+ girls versus 14.0 in HIV- girls (p=0.127). Among HIV+ adolescents, pubertal onset was persistently associated with age at ART initiation: across all measures for boys and girls, older age at ART initiation was strongly associated with later age of pubertal onset (p<0.05 for all measures), and children who initiated ART earlier ages had timing of pubertal onset that was comparable to that of HIV- controls (Figure). Later age of pubertal onset was also associated with lower current CD4 cell count (p<0.05 for all measures) but not with viral load or current PI vs NNRTI use. Conclusions: Differences in the timing of pubertal onset between HIV-infected adolescents and local HIV- controls may be less marked in this setting than has been observed in North America, and appear to be heavily modified by age at ART initiation.

Poster Abstracts

853

Left Heart Abnormalities in HIV-Infected Children in Harare, Zimbabwe Edith D. Majonga 1 ; Jon O. Odland 2 ; Rashida A. Ferrand 3 ; Katharina Kranzer 3 ; Grace McHugh 1 ; John Metcalfe 4 ;Tsitsi Bandason 1 ; Hilda Mujuru 5 ; Juan P. Kaski 6 1 Biomed Rsr and Training Inst, Harare, Zimbabwe; 2 The Arctic Univ of Norway, Tromsø, Norway; 3 London Sch of Hygiene & Trop Med, London, UK; 4 Univ of California San Francisco, San Francisco, CA, USA; 5 Univ of Zimbabwe, Harare, Zimbabwe; 6 Great Ormond Street Hosp & UCL Inst of Cardiovascular Sci, London, UK Background: Due to the remarkable scale-up of antiretroviral therapy (ART), HIV-infected children are expected to survive into adolescence and beyond. However, chronic complications such as cardiac abnormalities have become new challenges for this age-group. The main aim of this study was to characterise left sided cardiac abnormalities in a cohort of HIV-infected older children and adolescents taking ART.

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CROI 2016