Leukocyte Telomere Length at Birth and During the Early Life of Children Exposed to but Uninfected With HIV After In Utero Exposure to Antiretrovirals

Abstract

Background: Maternal combination antiretroviral therapy (cART) during pregnancy could impact the health of human immunodeficiency virus (HIV)-exposed, HIV-uninfected (HEU) children, because some antiretrovirals cross the placenta and can inhibit telomerase. Our objective was to compare leukocyte telomere length (LTL) in HEU children and HIV-unexposed, HIV-uninfected (HUU) children at birth and in early life and to investigate any relationship with cART exposure.

Methods: HEU and HUU children's blood LTL was compared cross-sectionally at birth, and during the first three years of life. Longitudinal HEU LTL dynamics was evaluated over that same period.

Results: At birth, the LTL in HEU children (n = 114) was not shorter than that in HUU children (n = 86), but female infants had longer LTL than male infants. Maternal cART (duration or type) showed no association with shorter infant LTL. Among 214 HEU children age- and sex-matched at a 1:1 ratio to HUU children, LTL declined similarly in both groups. In a longitudinal analysis, LTL attrition in HEU children was rapid from birth to 1 year of age and gradual thereafter. Zidovudine prophylaxis did not significantly alter LTL.

Conclusions: Our results indicate that from birth to 3 years of age, the LTL in HEU children is not negatively affected by exposure to maternal HIV infection and cART, at least not to the regimens used within this Canadian cohort, a reassuring finding.

Keywords: HIV-exposed uninfected; Leukocyte telomere length; combination antiretroviral therapy; longitudinal LTL attrition; maternal smoking during pregnancy.

Figure 1.

Unadjusted comparisons of leukocyte telomere length (LTL) at birth. A, Comparisons between human immunodeficiency virus (HIV)–exposed, HIV-uninfected (HEU) infants and HIV-unexposed, HIV-uninfected (HUU) infants. The P value was determined by the Mann-Whitney U test. B, Comparisons between males and females. The P values were determined by the Mann-Whitney U test. C, Comparisons between HEU children and HUU children with or without mothers who smoked during pregnancy. The P values were determined by the Mann-Whitney U test. D, Comparisons between HEU children exposed to different combination antiretroviral therapy regimens in utero and HUU children. The P values were determined by the Student t test (solid lines; P = .02, by analysis of variance, for the 3-group comparison involving HEU children exposed to the zidovudine [AZT] and lamivudine [3TC] backbone regimen) or the Kruskal-Wallis test (dashed line). For panels B–D, whiskers of the box plots represent the 5th–95th percentiles. ABC, abacavir; FTC, emtricitabine; LPV/r, ritonavir-boosted lopinavir; NFV, nelfinavir; NVP, nevirapine; NS, not significant; PI/r, ritonavir-boosted protease inhibitor; TDF, tenofovir disoproxil fumarate.

Figure 2.

Multivariable regression analyses of the association between possible predictors of leukocyte telomere length (LTL) at birth. A, Findings for all 185 participants (R² = 0.17). B, Findings for all 185 participants, with human immunodeficiency virus (HIV)–exposed, HIV-uninfected (HEU) children separated by type of combination antiretroviral therapy (cART) exposure in utero (R² = 0.20). C, Findings for 106 HEU children (R² = 0.19). D, Findings for 79 HIV-unexposed, HIV-uninfected (HUU) children (R² = 0.18). Effect sizes are expressed as nonstandardized β values. Strong collinearity between gestational age and birth weight was detected and precluded inclusion of both variables in the same model. Separate models that included either gestational age or birth weight were constructed, but the latter explained a greater portion of the variance (ie, it had a higher R²) and was chosen as the best model. ABC, abacavir; AZT, zidovudine; CI, confidence interval; FTC, emtricitabine; LPV/r, ritonavir-boosted lopinavir; NFV, nelfinavir; NVP, nevirapine; PI/r, ritonavir-boosted protease inhibitor; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine. ^aEight HEU children who were exposed to nonstandard cART regimen in utero were excluded from these analyses.

Figure 3.

Relationship between leukocyte telomere length (LTL) and age during the first 3 years of life among age- and sex-matched children. A, Findings for all human immunodeficiency virus (HIV)–exposed, HIV-uninfected (HEU) and all HIV-unexposed, HIV-uninfected (HUU) infants. B, Findings for HEU males and HUU males. C, Findings for HEU females and HUU females. D, Findings for HEU males and HEU females. E, Findings for HUU males and HUU females.

Figure 4.

A, Nonlinear regression model (ie, generalized mixed effects additive model) of leukocyte telomere length (LTL) and age (in weeks) for human immunodeficiency virus (HIV)–exposed, HIV-uninfected (HEU) infants. For clarity, one outlier (LTL value of 19.8) is omitted from the figure but not from the analysis. B, Linear regression model of LTL and age (in weeks) for HIV-unexposed, HIV-uninfected (HUU) children. The solid and dashed lines indicate the regression line and the 95% confidence interval of the estimated line, respectively. C, Comparisons of LTL at birth and the subsequent visit (at age 18–47 days) among HEU children. The P value was calculated by the paired Wilcoxon signed rank test.