Early ART Results in Greater Immune Reconstitution Benefits in HIV-Infected Infants: Working with Data Missingness in a Longitudinal Dataset

PLOS ONE, Dec 2019

Background Early initiation of anti-retroviral treatment (ART) decreases mortality as compared to deferred treatment, but whether it preserves immune cells from early loss or promotes their recovery remains undefined. Determination of complex immunological endpoints in infants is often marred by missing data due to missed visits and/or inadequate sampling. Specialized methods are required to address missingness and facilitate data analysis. Methods We characterized the changes in cellular and humoral immune parameters over the first year of life in 66 HIV-infected infants (0–1 year of age) enrolled in the CHER study starting therapy within 12 weeks of birth (n = 42) or upon disease progression (n = 24). A convenience cohort of 23 uninfected infants aged 0–6 months born to mothers with HIV-1 infection was used as controls. Flow cytometry and ELISA were used to evaluate changes in natural killer (NK) cells, plasmacytoid dendritic cells (pDC), and CD4+ or CD8+ T-cell frequencies. Data missingness was assessed using Little's test. Complete datasets for analysis were created using Multiple Imputation (MI) or Bayesian modeling and multivariate analysis was conducted on the imputed datasets. Results HIV-1-infected infants had greater frequency of CD4+ T cells with naïve phenotype, as well as higher serum IL-7 levels than HIV exposed/uninfected infants. The elevated data missingness was completely at random, allowing the use of both MI and Bayesian modeling. Both methods indicate that early ART initiation results in higher CD4+ T cell frequency, lower expression of CD95 in CD8+ T cell, and preservation of naïve T cell subsets. In contrast, innate immune effectors appeared to be similar independently of the timing of ART initiation. Conclusions Early ART initiation in infants with perinatal HIV infection reduces immune activation and preserves an early expansion of naïve T-cells with undiminished innate cell numbers, giving greater immune reconstitution than achieved with deferred ART. Both statistical approaches concurred in this finding.

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Early ART Results in Greater Immune Reconstitution Benefits in HIV-Infected Infants: Working with Data Missingness in a Longitudinal Dataset

December Early ART Results in Greater Immune Reconstitution Benefits in HIV-Infected Infants: Working with Data Missingness in a Longitudinal Dataset Livio Azzoni 0 1 Russell Barbour 0 1 Emmanouil Papasavvas 0 1 Deborah K. Glencross 0 1 Wendy S. Stevens 0 1 Mark F. Cotton 0 1 Avy Violari 0 1 Luis J. Montaner 0 1 0 1 The Wistar Institute, Philadelphia, Pennsylvania, United States of America, 2 Biostatistics Department, Yale School of Public Health , New Haven , Connecticut, United States of America, 3 Department of Molecular Medicine and Hematology, University of the Witwatersrand and National Health Laboratory Service , Johannesburg , South Africa , 4 Children's Infectious Diseases Clinical Research Unit, Department of Paediatrics and Child Health, Stellenbosch University , Cape Town , South Africa , 5 Perinatal HIV Research Unit, University of the Witwatersrand , Johannesburg , South Africa 1 Editor: Cristian Apetrei, University of Pittsburgh Center for Vaccine Research, UNITED STATES Early initiation of anti-retroviral treatment (ART) decreases mortality as compared to deferred treatment, but whether it preserves immune cells from early loss or promotes their recovery remains undefined. Determination of complex immunological endpoints in infants is often marred by missing data due to missed visits and/or inadequate sampling. Specialized methods are required to address missingness and facilitate data analysis. - Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was primarily supported by a grant to L.J. Montaner by the National Institute of Allergy and Infectious Disease (NIAID AI062512, www.niaid.nih.gov). Additional support was provided by The Philadelphia Foundation (Robert I. Jacobs Fund), https://www.philafound.org; The Stengel-Miller family, AIDS funds from the Commonwealth of Pennsylvania and from the Commonwealth Universal Research Enhancement Program (www.portal.state. pa.us/portal/server.pt/community/health_research_ Background Methods We characterized the changes in cellular and humoral immune parameters over the first year of life in 66 HIV-infected infants (0–1 year of age) enrolled in the CHER study starting therapy within 12 weeks of birth (n = 42) or upon disease progression (n = 24). A convenience cohort of 23 uninfected infants aged 0–6 months born to mothers with HIV-1 infection was used as controls. Flow cytometry and ELISA were used to evaluate changes in natural killer (NK) cells, plasmacytoid dendritic cells (pDC), and CD4+ or CD8+ T-cell frequencies. Data missingness was assessed using Little's test. Complete datasets for analysis were created using Multiple Imputation (MI) or Bayesian modeling and multivariate analysis was conducted on the imputed datasets. Results HIV-1-infected infants had greater frequency of CD4+ T cells with naïve phenotype, as well as higher serum IL-7 levels than HIV exposed/uninfected infants. The elevated data missingness was completely at random, allowing the use of both MI and Bayesian modeling. program_cure/14189), Pennsylvania Department of Health (www.health.pa.gov), as well as by the National Cancer Institute Wistar Cancer Center Grant (P30 CA10815, www.cancer.gov/). Dr. Barbour’s work was supported by NIMH grant 5P30MH062294-12 (https://www.nimh.nih.gov) to Paul Cleary, Dean of Yale’s School of Public Health. This grant supports the Center for Interdisciplinary Research on AIDS. Support for the CIPRA-SA CHER study was provided by the National Institute of Allergy and Infectious Diseases (NIAID, www.niaid.nih.gov) of the US National Institutes for Health (NIH), through the Comprehensive International Program of Research on AIDS (CIPRA) network, grant number U19 AI53217. The Departments of Health of the Western Cape (https://www.westerncape.gov.za/dept/health) and Gauteng (www.health.gpg.gov.za), South Africa and GlaxoSmithKline plc (www.gsk.com) provided additional support. The CIPRA-SA CHER study was conducted under the supervision of the USA Food and Drug Administration (IND n. 71494). The content of this publication does not necessarily reflect the views or policies of NIAID, nor does mention of trade names, commercial projects, or organizations imply endorsement by the US Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: GlaxoSmithKline plc (www. gsk.com) partially funded the CHER study by providing antiretroviral medications free of charge. No other compensation was provided from GlaxoSmithKline or any other commercial funders to the authors. This funding does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials. Both methods indicate that early ART initiation results in higher CD4+ T cell frequency, lower expression of CD95 in CD8+ T cell, and preservation of naïve T cell subsets. In contrast, innate immune effectors (...truncated)


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Livio Azzoni, Russell Barbour, Emmanouil Papasavvas, Deborah K. Glencross, Wendy S. Stevens, Mark F. Cotton, Avy Violari, Luis J. Montaner. Early ART Results in Greater Immune Reconstitution Benefits in HIV-Infected Infants: Working with Data Missingness in a Longitudinal Dataset, PLOS ONE, 2015, Volume 10, Issue 12, DOI: 10.1371/journal.pone.0145320