Infectious morbidity of breastfed, HIV-exposed uninfected infants under conditions of universal antiretroviral therapy in South Africa: a prospective cohort study

Abstract

Background: Without breastfeeding and maternal antiretroviral therapy (ART), HIV-exposed uninfected (HEU) infants have greater infectious morbidity than HIV-unexposed (HU) infants. We hypothesised that with the introduction of universal maternal ART, breastfed HEU and HU infants would have similar morbidity.

Methods: We prospectively studied a cohort of HIV-infected pregnant women initiating ART, and a parallel group of HIV-uninfected pregnant women, starting from their first antenatal care visit at the Gugulethu Midwife Obstetrics Unit in Cape Town, South Africa. All pregnant women attending their first antenatal care visit were eligible for enrolment if aged 18 years or older and planning to deliver in Cape Town, without gestational age restrictions. HIV-infected women were participants of the Maternal Child Health ART (MCH-ART) study, and HIV-uninfected women were participants of the HIV-Unexposed Uninfected (HU2) study. All enrolled women were followed up during pregnancy and through delivery. At the early neonatal visit (scheduled for the first week after birth), mother-infant pairs who practiced any breastfeeding in the first 7 days of life were eligible for further postnatal follow-up for at least 12 months post partum. HIV infection was excluded among HEU infants at ages 6 weeks and 12 months by PCR. We evaluated the effect of HIV exposure on two primary outcomes: hospitalisation (all-cause and infection-related admission to hospital) and longitudinal prevalence of child infectious illness (diarrhoea and presumed lower respiratory tract infection [LRTI]). Hospitalisation data were abstracted from routine health records. Crude and adjusted incidence rate ratios (aIRRs; with adjustment for maternal HIV disease severity, timing of ART initiation, breastfeeding, timely vaccination, and birth outcomes [gestational size and age]) for infection-related hospitalisations were calculated from Poisson regression models (with variance corrected for clustering). Prevalence of infant infectious illness was based on maternal self-report for the preceding 2 weeks of each visit, with questions based on Demographic and Health Survey (DHS) questionnaires. Infants who acquired HIV infection during follow-up were excluded from this analysis. MCH-ART is registered on ClinicalTrials.gov, NCT01933477.

Findings: Pregnant women were recruited between March 20, 2013, and Aug 19, 2015. Mother-infant pairs (HEU, n=459; HU, n=410) were followed up for a median of 12 months until March 24, 2017. Compared with HU infants, HEU infants had more infection-related hospitalisations between the age of 8 days and 3 months (HEU, 34·2 admissions per 100 child-years [24·4-47·9] vs 9·8 per 100 child-years [95% CI 5·1-18·8]; IRR 3·50 [95% CI 1·68-7·30]), but rates were similar at other ages. In infants aged 8 days to 3 months, infection-related hospitalisations for HEU infants with healthier mothers (n=84; ART initiation at <24 weeks' gestation, CD4 count >350 cells per μL, HIV viral load <4·0 log₁₀ copies per mL: 15·88 admissions per 100 child-years [5·12-49·23]) approximated those of HU infants (9·77 per 100 child-years [5·08-18·78]; aIRR 1·28 [0·27-6·05]). HEU infants of mothers with late ART initiation (at ≥24 weeks' gestation) and advanced disease (CD4 count ≤350 cells per μL and HIV viral load ≥4·0 log₁₀ copies per mL; n=44) had the highest admission rate (40·44 per 100 child-years [15·18-107·74]; aIRR 5·01 [1·50-16·71]). In this age group, reduced admissions were seen in HEU infants with optimal breastfeeding (initiated within 1 h of birth and exclusive through age 3 months) and timely vaccination (required doses received within 2 weeks of indicated age; n=90; 9·63 admissions per 100 child-years [2·41-38·49]). Between birth and age 6 months, HEU infants had an almost five times greater prevalence of LRTIs than HU infants (aPR 4·69 [2·40-9·17]), and a three-times greater prevalence of diarrhoeal illness (aPR 2·93 [1·70-5·07]). After age 6 months, these associations were ameliorated.

Interpretation: Despite ART in pregnancy, breastfed HEU infants versus breastfed HU infants had transiently increased infectious morbidity risks in early infancy. However, differences were driven by factors potentially amenable to intervention, including delayed diagnosis and ART initiation in HIV-positive mothers, and suboptimal breastfeeding and vaccination of their infants.

Funding: US National Institute of Child Health and Human Development, Elizabeth Glaser Pediatric AIDS Foundation, South African Medical Research Council, Fogarty Foundation and the Office of AIDS Research.

FIGURE 1.

Study flow

FIGURE 2.

Infection-related hospitalizations comparing HIV-exposed uninfected and HIV-unexposed children over time: distribution of diagnoses and incidence over time 2A. Infection-related causes for hospitalization: distribution by HIV exposure and age category Legend: HEU, HIV-exposed uninfected; HU, HIV-unexposed uninfected; d, days; m, months; LRTI, lower respiratory tract infection (includes pneumonia and bronchiolitis); TB, pulmonary tuberculosis; Percentages based on number of admissions divided by number of children in category 2B.Infection-related hospitalization: incidence rates and rate ratios comoaring HIV-exposed uninfected to HIV-unexposed children over time Legend: HEU, HIV-exposed uninfected children; HU, HIV-unexposed chidren; d, days; m, months; IRR, incidence rate ratio from Poisson regression models adjusted for clustering; Cl, confidence internal. Muitivariable models adjusted for socio-economic factors (access to flush toilet and running water inside the home). maternal depression, preterm birth, child underweight, vaccination status. quality of breastfeeding and season at birth Sampie size per age internal: <7 days, N=869; 7 days-3 months, N=849; 3–6 months, N=808; 6–9 months, N=782; 9–12 months, N=745; >12 months, N=664

FIGURE 2.

Infection-related hospitalizations comparing HIV-exposed uninfected and HIV-unexposed children over time: distribution of diagnoses and incidence over time 2A. Infection-related causes for hospitalization: distribution by HIV exposure and age category Legend: HEU, HIV-exposed uninfected; HU, HIV-unexposed uninfected; d, days; m, months; LRTI, lower respiratory tract infection (includes pneumonia and bronchiolitis); TB, pulmonary tuberculosis; Percentages based on number of admissions divided by number of children in category 2B.Infection-related hospitalization: incidence rates and rate ratios comoaring HIV-exposed uninfected to HIV-unexposed children over time Legend: HEU, HIV-exposed uninfected children; HU, HIV-unexposed chidren; d, days; m, months; IRR, incidence rate ratio from Poisson regression models adjusted for clustering; Cl, confidence internal. Muitivariable models adjusted for socio-economic factors (access to flush toilet and running water inside the home). maternal depression, preterm birth, child underweight, vaccination status. quality of breastfeeding and season at birth Sampie size per age internal: <7 days, N=869; 7 days-3 months, N=849; 3–6 months, N=808; 6–9 months, N=782; 9–12 months, N=745; >12 months, N=664

FIGURE 3.

Incidence rate ratios of infection-related hospitalization between 7 days and 3 months of age comparing HIV-exposed uninfected to HIV-unexposed children 3A. Variation by maternal HIV disease severity and gestation at ART initiation in pregnancy Legend: IRR, crude incidence rate ratio from Poisson regression analiysis corrected for clustering; aIRR, incidence rate ratios adjusted for access to flush toilet and running water, postpartum depression, preterm birth, season at birth, being underweight in a previous age interval, quality of breastfeeding (early initiation and Exclusivity in the first 3 months) and vaccination status Reference group includes all HU children (N=405) HEU categories (CD4 tell count and HIV viral load category boundaries set at group median value): “Mild” (N=84): pre-ART maternal CD4 cell count > 350 cells/mm³ AND HIV viraI load <4·0 log¹⁰ copies/mL AND ART initiated prior to 24 weeks’ gestation in pregnancy (vs HU, aIRR 1–28, 95% CI 0·27-6·05) “Moderate” (N=320): pre-ART maternal CD4 cell court ≤ 350 cells/mm³ OR HIV viral load ≥4·0 log₁₀ copies/mL but ART initiated prior to 24 weeks’ gestation in pregnancy, OR, maternal CD4 cell count > 350 cells/mm³ OR HIV viral load <4·0 log₁₀ copies/mL but ART initiation at or after 24 weeks’ gestation in pregnancy (vs HU, aIRR 3.79, 95% CI 1·75–8.18] “Severe: (N=44): pre-ART maternal CD cell count ≤350 AND HIV viral load ≥4·0 log₁₀ copies/mL AND ART initiation at or after 24 weeks’ gestation in pregnancy (vs HU, aIRR 5·01,95% CI 1·50–16·71) 3B: Variation by quality of breastfeeding and timelines of vaccination in the first 3 months of life Legend: IRR, crude incidence rate ratio from Poisson regression analysis corrected for clustering; aIRR, incidence rate ratios adjusted for access to flush toilet and running water, postpartum depression, preterm birth, season at birth and being underweight in a previous age interval; “Optimal breastfeedng” defined as initiation within 1 hour of birth and exclusive breastfeeding through 3 months of age; vaccinations considered timely if all required doses received within 2 weeks of indicated age (based on 6 and 10 weeks’ South African schedule} Reference category includes all HU children (N=405) HEU categories: BF+ V+: Optimal breastfeeding and timely vaccination (N=90); vs HU, aIRR 0.86, 95% CI 0.19–4.00 BF+ V−: Optimal breastfeeding but delayed or incomplete vaccination (N=14); vs HU, aIRR 2.62, 95% CI 0.32–21.26 BF− V+: Suboptimal breastfeeding but timely vaccination (N=187); vs HU, aIRR 4.15, 95% CI 1.88–9.15 BF− V−: Suboptimal breastfeeding and delayed or incomplete vaccination (N=50); vs HU, aIRR 5.24, 95% CI 1.94–14.14

FIGURE 3.

Incidence rate ratios of infection-related hospitalization between 7 days and 3 months of age comparing HIV-exposed uninfected to HIV-unexposed children 3A. Variation by maternal HIV disease severity and gestation at ART initiation in pregnancy Legend: IRR, crude incidence rate ratio from Poisson regression analiysis corrected for clustering; aIRR, incidence rate ratios adjusted for access to flush toilet and running water, postpartum depression, preterm birth, season at birth, being underweight in a previous age interval, quality of breastfeeding (early initiation and Exclusivity in the first 3 months) and vaccination status Reference group includes all HU children (N=405) HEU categories (CD4 tell count and HIV viral load category boundaries set at group median value): “Mild” (N=84): pre-ART maternal CD4 cell count > 350 cells/mm³ AND HIV viraI load <4·0 log¹⁰ copies/mL AND ART initiated prior to 24 weeks’ gestation in pregnancy (vs HU, aIRR 1–28, 95% CI 0·27-6·05) “Moderate” (N=320): pre-ART maternal CD4 cell court ≤ 350 cells/mm³ OR HIV viral load ≥4·0 log₁₀ copies/mL but ART initiated prior to 24 weeks’ gestation in pregnancy, OR, maternal CD4 cell count > 350 cells/mm³ OR HIV viral load <4·0 log₁₀ copies/mL but ART initiation at or after 24 weeks’ gestation in pregnancy (vs HU, aIRR 3.79, 95% CI 1·75–8.18] “Severe: (N=44): pre-ART maternal CD cell count ≤350 AND HIV viral load ≥4·0 log₁₀ copies/mL AND ART initiation at or after 24 weeks’ gestation in pregnancy (vs HU, aIRR 5·01,95% CI 1·50–16·71) 3B: Variation by quality of breastfeeding and timelines of vaccination in the first 3 months of life Legend: IRR, crude incidence rate ratio from Poisson regression analysis corrected for clustering; aIRR, incidence rate ratios adjusted for access to flush toilet and running water, postpartum depression, preterm birth, season at birth and being underweight in a previous age interval; “Optimal breastfeedng” defined as initiation within 1 hour of birth and exclusive breastfeeding through 3 months of age; vaccinations considered timely if all required doses received within 2 weeks of indicated age (based on 6 and 10 weeks’ South African schedule} Reference category includes all HU children (N=405) HEU categories: BF+ V+: Optimal breastfeeding and timely vaccination (N=90); vs HU, aIRR 0.86, 95% CI 0.19–4.00 BF+ V−: Optimal breastfeeding but delayed or incomplete vaccination (N=14); vs HU, aIRR 2.62, 95% CI 0.32–21.26 BF− V+: Suboptimal breastfeeding but timely vaccination (N=187); vs HU, aIRR 4.15, 95% CI 1.88–9.15 BF− V−: Suboptimal breastfeeding and delayed or incomplete vaccination (N=50); vs HU, aIRR 5.24, 95% CI 1.94–14.14