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

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.

Below:  Statistical analysis summary.

The tree represents the statistical analyses applied in the order in which they were performed. Distribution assumptions are indicated. Statistical packages are listed; where not specified, tests were conducted using R.

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By:   

Livio Azzoni, Emmanouil Papasavvas, Luis J. Montaner

The Wistar Institute, Philadelphia, Pennsylvania, United States of America

Russell Barbour

Biostatistics Department, Yale School of Public Health, New Haven, Connecticut, United States of America

Deborah K. Glencross, Wendy S. Stevens

Department of Molecular Medicine and Hematology, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa

Mark F. Cotton

Children’s Infectious Diseases Clinical Research Unit, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa

Avy Violari

Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa

  

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