CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

interruptions in children also cause a rapid reduction in CD4+ T cells but with less clinical impact and with good CD4+ T cell restoration following ART reintroduction. In contrast to adults, who predominantly reconstitute their T cells from the peripheral cell population, children have a great capacity for immune reconstitution mainly from the thymus. In this study, we have investigated ART interruption in children with HIV to determine the impact on thymic output, peripheral T cell proliferation, TCR diversity and clonality. Methods: TCR repertoire and TCR clonotypes was estimated by Next Generation Sequencing techniques in purified naive CD4+ T cells and memory CD8+ T cells. Thymic output was measured using a mathematical model, combining naive CD4+ T-cell proliferation rates with DNA PCR quantification of TCR excision circles, and IL-8, a chemokine released from naive T cells. Samples from 8 HIV-infected children were available for this study from a randomized controlled trial where one cohort remained on ART and the other had treatment withdrawn for 48 weeks. Results: Thymic output was found to increase rapidly when ART was stopped. The increase in thymic output was associated with increased peripheral T cell proliferation, both returning to pre-interruption levels when the children re-started ART. TCR repertoire diversity and clonotype profiles appeared to be similar before treatment interruption and 3 years after ART re-introduction in both naive CD4+ T cells and memory CD8+ T cells. Specific clonotypes were seen to expand and being highly shared in the naïve CD4+ T cell population in response to ART interruption. There was no difference observed in these immune parameters in the HIV children receiving continuous treatment between baseline and end of study. Conclusion: Importantly we found that thymic output, peripheral cell expansion, TCR repertoire and clonotypic profiles return to pre-interruption levels. This indicates that the high levels of thymic output in children may be sufficient to reverse the impact of ART cessation. 810 HIGH CMV DNAAEMIA ASSOCIATES WITH STUNTING AND CHRONIC LUNG DISEASE IN HIV+ CHILDREN Louis-Marie Yindom 1 , Victoria Simms 2 , Edith D. Majonga 2 , Grace McHugh 3 , Ethel Dauya 3 , Tsitsi Bandason 3 , Helene Vincon 1 , Jamie Rylance 4 , Shungu Munyati 3 , Rashida Ferrand 2 , Sarah Rowland-Jones 1 1 University of Oxford, Oxford, UK, 2 London School of Hygiene & Tropical Medicine, London, UK, 3 Biomedical Research and Training Institute, Harare, Zimbabwe, 4 Liverpool School of Tropical Medicine, Liverpool, UK Background: Long-term survival of children with perinatally acquired HIV (PHIV) - even in those stable on antiretroviral therapy (ART) - is associated with significant health problems that are not typical of HIV-associated opportunistic infections or AIDS-defining illnesses. In sub-Saharan Africa, older children and adolescents with PHIV experience a range of chronic complications including growth impairment, chronic lung disease (CLD), cardiac abnormalities, pubertal delay and neurocognitive disorders. Moreover, the beta herpes virus, cytomegalovirus (CMV), is ubiquitous in Africa, infecting all children by age 18 months. We hypothesised that CMV reactivation might play a role in the poor health of older children with PHIV and we examined the associations between uncontrolled co-infection with CMV and comorbidities including lung function and growth. Methods: Plasma samples were isolated from two cohorts of older children and adolescents aged 6-16 years with PHIV (n=394) and HIV negative controls (n=224). The HIV-infected children were either newly diagnosed (hence untreated), or known to be HIV-infected and stable on antiretroviral therapy (ART). CMV DNA-aemia was measured using quantitative polymerase chain reaction (qPCR). We used longitudinal mixed-effects logistic regression to model CMV DNA-aemia as a time-varying outcome. Results: At enrolment, CMV DNA-aemia ≥1000 copies/ml (defined as “clinically significant”) was detected in 5.8% of uninfected children, 14.1% of HIV-infected participants stable on ART and 22.5 % of the HIV-infected ART-naïve children (Chi2 = 23.4, p<0.001). The prevalence of clinically significant CMV DNA-aemia was associated with CD4 count below 350 cells/µl. Amongst HIV-infected ART- naïve children, CMV DNA-aemia ≥1000 copies/ml was independently associated with reduced lung function (adjusted odds ratio aOR=3.15, 95%CI: 1.20-8.28, p=0.02). Amongst ART-treated children, stunting was associated with CMV DNA-aemia ≥1000 copies/ml (aOR=2.79, 95%CI: 0.97-8.02, p=0.057). Conclusion: Clinically significant CMV DNA-aemia was common in older children and adolescents with PHIV, even amongst those stable on ART,

suggesting a role for inadequately controlled CMV infection in the pathogenesis of the chronic complications of PHIV in Africa. 811 IMMUNE IMBALANCE IS ASSOCIATED WITH IMPAIRED SPIROMETRY IN PERINATALLY ACQUIRED HIV Engi F. Attia 1 , Denise Jacobson 2 , Wendy Yu 2 , Elizabeth Maleche Obimbo 3 , Paige L. Williams 2 , Claudia Crowell 4 , Michael H. Chung 1 , Kristina Crothers 1 , William T. Shearer 5 , for the Pediatric HIV/AIDS Cohort Study 1 University of Washington, Seattle, WA, USA, 2 Harvard University, Boston, MA, USA, 3 University of Nairobi, Nairobi, Kenya, 4 Seattle Children’s Hospital, Seattle, WA, USA, 5 Baylor College of Medicine, Houston, TX, USA Background: Chronic lung disease (CLD) is increasingly recognized among youth living with perinatally-acquired HIV (PHIV) worldwide. Yet, pathophysiologic mechanisms of CLD in PHIV youth are largely unknown. We hypothesized that immune imbalance and activation based on a high CD8 T-cell count and low CD4/CD8 ratio are associated with impaired lung function in PHIV, and explored whether lung function differed between youth living in a high- income and a low-and-middle-income setting. Methods: We performed a cross-sectional analysis of PHIV youth (10-21 years old) in the U.S. Pulmonary Complications in the Pediatric HIV/AIDS Cohort (PCPA) Study (n=188) and Kenyan BREATHE I Study (n=49). Sociodemographic, clinical, immune function, and spirometry data were ascertained within 3 months of enrollment. In U.S. and Kenyan youth combined, we estimated Spearman partial correlations of CD8 and CD4/CD8 with pre- and post-bronchodilator (BD) %-predicted forced expiratory volume in one second (FEV1%), adjusted for age and sex. We also fit linear regression models to evaluate mean differences (95%CI) in FEV1% by study site, adjusted for age, sex, and CD8 (or CD4/CD8 in separate models). Results: Kenyan youth were younger, and a higher percent had prior pulmonary infections and passive cigarette smoke exposure (Table). Although Kenyan youth had later antiretroviral therapy (ART) initiation, Kenyan and U.S. youth had similar distributions of ART use and recent CD4. Nonetheless, Kenyan youth had significantly higher CD8 and lower CD4/CD8 ratio. Overall, correlations of CD8 with pre- and post-BD FEV1%were -0.25 (p<0.001) and -0.22 (p<0.001), and correlations of CD4/CD8 with pre- and post-BD FEV1%were 0.28 (p<0.001) and 0.26 (p<0.001). In adjusted linear regression models, pre-BD [-9.6 (95%CI -15.4, -3.8); p=0.001] and post-BD [-8.3 (95%CI -14.0, -2.7); p=0.004] FEV1%were lower in Kenyan compared to U.S. youth. These differences were attenuated in models also adjusting for CD8 (pre-BD: [-5.2 (95%CI -11.6, 1.2); p=0.11]; post-BD: [-4.5 (95% CI -10.7, 1.8); p=0.16]); associations were similar in models adjusted for CD4/CD8. Conclusion: High CD8 and low CD4/CD8 were associated with greater spirometry impairment. Further, Kenyan PHIV youth had lower lung function measures than U.S. PHIV youth, and this association was attenuated by adjusting for CD8 or CD4/CD8. Our findings suggest that chronic immune imbalance and activation may contribute to CLD in PHIV despite ART use with associated CD4 reconstitution.

Poster Abstracts

812 ENDOTHELIAL DYSFUNCTION IN SOUTH AFRICAN YOUTH WITH PERINATALLY ACQUIRED HIV ON ART

Sana Mahtab 1 , Heather Zar 1 , Susan J. Joubert 1 , Nana Akua Asafu-Agyei 1 , Norme J. Luff 1 , Nomawethu Jele 1 , Liesl Zülke 1 , Landon Myer 1 , Jennifer Jao 2

CROI 2019 315