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Objective:To assess the impact of HIV and antiretroviral exposure without infection on lung growth and function over the first 2 years of life.Design:Prospective observational study of an African birth cohort, Drakenstein Child Health Study.Method:Infants enrolled antenatally had lung function measured at 6 weeks, 1 and 2 years. HIV-infected women received antiretroviral therapy (ART) as per local guidelines. The association between HIV and antiretroviral exposure with lung function was assessed using mixed effects modelling.Results:Of 1143 infants born, two HIV-infected infants were excluded from analysis; 909 (80%) infants had lung function collected at 6 weeks [190 (21%) were HIV-exposed uninfected (HEU)]; 782 (69%) at 1 year and 741 (65%) at 2 years. At 6 weeks HEU infants had larger tidal volume compared with HIV-unexposed infants (1.13ml, confidence interval: 0.02-2.23, P=0.045). High maternal viral load was associated with a 17% lower expiratory flow over 2 years (0.17, confidence interval 0.00-0.34, P=0.046). First-line ART initiated during pregnancy was associated with lower infant tidal volume at 6 weeks compared with those who initiated ART before pregnancy (-2.7ml, -5.31 to -0.10, P=0.042), and low maternal CD4+ cell counts associated with lower infant tidal over 2 years (-11.1ml, -18.58-3.58, P=0.004).Conclusion:HIV exposure is associated with altered lung function in early life, with a vulnerable HEU subgroup based on maternal disease severity, immunological compromise and ART exposure. These data highlight the importance of ongoing surveillance of respiratory health in HEU children.
This is a study of HIV-exposed uninfected and HIV-unexposed infants enrolled in the DCHS and who were followed from birth through to 2 years, with lung function measured at 6 weeks, 1 year and 2 years. The DCHS is a birth cohort study situated in a peri-urban, low socioeconomic area outside Cape Town in South Africa [18]. Mothers were enrolled antenatally between March 2012 and March 2015 and followed through pregnancy at one of two primary care clinics with mother–child pairs followed from birth. Infants attended scheduled study visits at 6, 10, 14 weeks and 6, 9 and 12 months of age and 6 monthly thereafter. In addition to these regular health assessments and monitoring, a strong surveillance system was established for the detection of lower respiratory tract illness (LRTI). Socioeconomic status was assessed as a composite variable, placing participants into relative quartiles. This score is derived from employment status and standardized scores of educational attainment, household income, assets and market access [19]. The study was approved by the Faculty of Health Sciences, Human Research Ethics Committee, University of Cape Town (401/2009; 423/2012) and by the Western Cape Provincial Health Research Committee. Parents gave informed, written consent in their first language for their infants to participate. Maternal HIV infection was assessed at enrolment through self-report and routine prevention of mother-to-child transmission (PMTCT) HIV testing. All HIV-infected mothers received antiretroviral according to the Western Cape Department of Health Guidelines for PMTCT at the time. In 2012, the guidelines advised zidovudine (ZDV) in all pregnant women and ART to be initiated as per maternal clinical/immunological status. From early-2013 onwards the current guidelines were introduced which are triple ART irrespective of clinical status, made up of one nonnucleoside reverse transcriptase inhibitor and two nucleoside reverse transcriptase inhibitors [typically efavirenz (EFV) and tenofovir (TDF) and emtricitabine (FTC)/lamivudine] [20]. HIV data were obtained from folder reviews of mothers and children and accessing electronic laboratory data from the National Health Laboratory Service as well as self-report interviews antenatally and postnatally. In the case of multiple measures, the lowest recorded CD4+ cell count (collected 1 year before to 3 months after birth to maximise numbers) and highest viral load during pregnancy were used. HIV-exposed children were tested for HIV at 6 weeks (by PCR), 9 months (by PCR, ELISA or rapid antibody testing) and 18 months (by rapid antibody testing), as per provincial PMTCT guidelines. Lung function testing was undertaken first at 6 (5–11) weeks of age corrected for prematurity (<37 weeks) and then at 1 year (11–13 months) and 2 years (23–25 months). All testing was done in unsedated, behaviourally assessed quiet sleep as previously described [21,22]. Lung function tests included measures of tidal breathing (tidal volume, respiratory rate, expiratory flow ratios) and sulphur-hexafluoride (SF6) multiple breath washout (MBW), which measures functional residual capacity (FRC) and the lung clearance index (LCI). The tidal lung volumes are a measure of lung growth. Low expiratory flow ratio [time to peak tidal expiratory flow over total expiratory time (tPTEF/tE)] reported here is associated with airway obstruction, though is also affected by lung size and breathing control [23]. The LCI is an early measure of small airways disease and impaired ventilation, it increases in disease states [24]. Measurements were collected using the Exhalyser D with ultrasonic flow meter (Ecomedics AG, Duernton, Switzerland) with 4% SF6 for the MBW [21]. Analyses were conducted with STATA version 14.0 (College Station, Texas, USA). Descriptive data were presented as means, SDs and frequencies (proportions), as appropriate. Mann–Whitney rank sum tests was used to test for significant differences between categorical and continuous variables. Pearson chi-square test or Fisher Exact tests were used to determine if significant differences existed between categorical variables. Lung function outcomes were modelled using linear regression to assess the impact of HIV exposure, maternal HIV disease severity and antiretroviral exposure on the lung function attained at each time point. Maternal HIV viral load was used as a categorical variable: undetectable (1000 copies/ml). Maternal CD4+ cell count was categorized as more than 500, 350–500 and 350 cells/μl or less. BMI for age z-scores were calculated using the WHO Child Growth Standards ‘Igrowup’ STATA package. Base models were first constructed using Directed Acyclic Graphs (DAGs) for confounder selection. DAGs minimal adjustment set of variables [socioeconomic status (SES), race, sex, BMI for age, maternal smoking] were used to assess the impact of exposures on lung function outcomes at each time point (6 weeks, 12 months and 24 months). In addition, mixed effects models were used to assess the impact of HIV and antiretroviral exposure on lung growth over 2 years. In this model LRTI episodes during 2 years was included given the documented impact of LRTI on lung function outcomes in this cohort [25]. For antiretroviral exposure, analyses were performed comparing all those children exposed to maternal triple ART, compared with ZDV, only. However, for timing of ART initiation we limited to the first-line regimen that the majority of women were receiving in the study (TDF/FTC/EFV) which is currently WHO recommended first-line in our setting (dolutegravir is not yet widely available), and by limiting to one regimen we were able to better examine the effects of timing without the confounding effects of different antiretroviral drugs. Estimated coefficients, 95% confidence intervals (CIs) and P values were recorded for each early life exposure of interest. In addition, diagnostic checks were conducted. These included checking for normality in the residuals using histograms, standardized probability (P–P) plot, Quantile–Quantile (Q–Q) plots, as well the Shapiro–Wilk W test for normality. Further, homoscedasticity was checked using scatter plots and the presence of multicollinearity was explored using the variance inflation factor. Three of the lung function measures (FRC, ratio of time to peak tidal expiratory flow over total time of expiration and respiratory rate) were found to be nonnormal, and thus log-transformations were performed on these outcomes.
