Effects of HIV exposure, TB and HIV treatment, and isoniazid preventive therapy on prognosis and growth trajectories of children

Introduction: Expanded access to antiretroviral therapy (ART) and prevention of mother-to-child transmission of HIV services (PMTCT) have enabled the vast majority of pregnant women living with HIV (WLWH) to give birth to HIV-exposed uninfected (HEU) children. Evidence suggests that birth weight and birth length are lower in HEU than in HIV unexposed uninfected (HUU) children, but there is conflicting evidence on growth after birth. HEU children have a high risk of Mycobacterium tuberculosis (Mtb) infection and TB disease, with an increased risk of exposure to known (mothers living with HIV) and unknown sources of infection. Latent TB infection (LTBI) can be effectively treated with isoniazid preventive therapies (IPT). Recently completed randomized controlled trials have examined IPT’s efficacy and effectiveness in preventing TB infection and disease in pregnant mothers and infants, but the long-term effects of IPT exposure in utero or during infancy on infant growth are unknown. Despite ART and PMTCT, some children still get infected with HIV. Children living with HIV (CHIV) have a high mortality rate, particularly if diagnosed late. TB is one of the most common infections in CHIV. Treating both TB and HIV is vital to decreasing TB-related mortality in CHIV. However, TB-HIV co-treatment poses management challenges and potential effects on childhood growth. The goals of the study are to evaluate the effects of HIV exposure, TB-HIV treatment, and IPT on the prognosis and growth trajectories of children. The project had four aims: Aim 1: To determine the effect of HIV and ART exposure in-utero on growth and development of HEU infants. Aim 2. To determine the effect of maternal pregnancy versus postpartum maternal IPT on growth faltering of HEU infants. Aim 3: To evaluate the impact of infant IPT on the rate of growth of HEU infants. Aim 4: To determine the effect of TB-HIV co-treatment on the prognosis (viral load suppression, immune reconstitution, and growth). Methods: This dissertation used four data sources to address the aims of the study. To address Aim #1, we used data from a prospective birth cohort (MiTIPS) of women with and without HIV infection, and their infants in Western Kenya. Infants were enrolled at 6 weeks of age and followed until 24 months of age. We used multivariable linear mixed-effects models to compare growth rates (weight-for-age z-score [WAZ] and height-for-age z-score [HAZ]) and multivariable linear regression to compare overall development z-score between HEU and HIV-unexposed uninfected (HUU) children. To address Aim #2, we used a post-hoc analysis of data from TB APPRISE, a multicenter, double-blind, placebo-controlled trial, which randomized women with HIV to 28-weeks of IPT starting in pregnancy (pregnancy-IPT) or postpartum week 12 (postpartum-IPT). Infants were followed from birth to 48 weeks of age. We used overall and sex-stratified multivariable Cox proportional hazards regression to compare time to infant growth faltering between arms to 12 weeks and 48 weeks postpartum. To address Aim #3, we used data from The infant TB Infection Prevention Study (iTIPS) trial, a non-blinded RCT of IPT versus no IPT among HIV-exposed infants in Kenya. Infants were enrolled at 6 months. Interventions were given for 12 months and observational follow-up continued until 24 months of age. We used intent-to-treat linear mixed-effects models to compare growth rates (weight-for-age z-score [WAZ] and height-for-age z-score [HAZ]) between trial arms. To address Aim #4, we used longitudinal data from the PUSH trial among ART-naïve 0-12 years of age hospitalized CHIV (NCT02063880) in Kenya. TB-ART treated and ART-only groups were compared at 6-months post-ART for viral suppression (<40 c/ml), CD4% change, and growth using generalized linear models, linear regression, and linear mixed-effects models, respectively. Results: Aim #1: Among 355 infants, 184 were HEU children, 51.3% (182/355) were female, 3.9% (14/355) were low birthweight, and 8.5% (26/307) were preterm. Median maternal age was 25.0 (interquartile range [IQR] 22.0-29.0 years); mothers of HEU children were older and had higher income; all mothers of HEU children received ART in pregnancy, of whom 67.9% (125/184) started ART pre-pregnancy and 87.3% (158/181) received 3TC/FTC, TDF, EFV regimens. In longitudinal linear analyses, HEU children did not differ significantly from HUU in growth or development (p>0.05 for all). Higher maternal education was associated with significantly better growth and development in all children in the first 24 months of age: WAZ (β=0.18 [95% CI:0.01, 0.34]), HAZ (β=0.26 [95% CI: 0.04, 0.48], and overall development (β=0.24 [95% CI: 0.02, 0.46]). Breastfeeding was associated with significantly better HAZ (β=0.42 [95% CI: 0.19, 0.66]) and development (β=0.31 [95% CI: 0.08, 0.53]) in all children. Aim #2: Among 898 HIV-exposed uninfected (HEU) infants, 447 (49.8%) were females. Infants in the pregnancy-IPT arm had a 1.47-fold higher risk of becoming underweight by 12 weeks of age (aHR 1.47 [95% CI: 1.06, 2.03]) than infants in the postpartum-IPT arm; increased risk persisted to 48 weeks postpartum (aHR 1.34 [95% CI: 1.01, 1.78]). Maternal IPT timing was not associated with stunting or wasting. In sex-stratified analyses, male infants in the pregnancy-IPT arm experienced an increased risk of lower birthweight (LBW) (aRR 2.04 [95% CI: 1.16, 3.68), preterm birth (aRR 1.81 [95% CI: 1.04, 3.21]) and becoming underweight by 12 weeks (aHR 2.02 [95% CI: 1.29, 3.18]) and 48 weeks (aHR 1.82 [95% CI: 1.23, 2.69]). Maternal IPT timing did not influence growth in female infants. Aim #3: Among 298 infants, 150 were randomized to IPT between 6-10 weeks of age, 47.6% were females, median birthweight was 3.4 kg (inter-quartile range [IQR] 3.0-3.7), and 98.3% were breastfed. During 12-month IPT treatment and 12-month post-RCT follow-up, WAZ and HAZ declined significantly with more HAZ decline in male infants. There were no growth differences between trial arms, including in sex-stratified analyses. In longitudinal linear analysis, mean WAZ (β=0.04 [95% CI:-0.14, 0.22]), HAZ (β=0.14 [95% CI:-0.06, 0.34]), and WHZ [β=-0.07 [95% CI:-0.26, 0.11]) z-scores were similar between arms as were WAZ and HAZ growth trajectories. Infants in the IPT arm had a higher monthly WHZ increase (β to 24 months 0.02 [95% CI:0.01, 0.04]) than in the no-IPT arm. Aim #4: Among 152 CHIV, 40.8 % (62) were TB-ART treated. At baseline pre-ART, median age was 2.0 years, VL was 5.6 log10 c/ml, CD4% was 14%, and 40.4% had HAZ<2; CD4% and growth measures were significantly lower, and VL significantly higher in the TB-ART group. At 6 months post-ART, 37.2% had viral suppression and the median (IQR) CD4% increased by 7.2% (2.0%-11.6%) CD4% with no difference between TB-ART and ART-only groups. The TB-ART group had significantly lower WAZ and HAZ throughout follow-up (WAZ -0.81 [95% CI: -1.23, -0.38, p<0.001], HAZ -0.15 [95% CI: -0.29, -0.01, p=0.030]). The TB-ART group had greater rate of WAZ increase in analyses unadjusted and adjusted for baseline WAZ (unadj 0.62 [95% CI: 0.18, 1.07, p=0.006] or adj 0.58 [95% CI: 0.12, 1.03, p=0.013]). Conclusion: HEU children had a similar growth trajectory and development compared with HUU children. Breastfeeding and maternal education improved weight, height, and overall development of children, suggesting that these factors are more influential than HIV or ART exposure on infant growth in this cohort with universal maternal ART coverage for HEU. Maternal IPT during pregnancy was associated with an increased risk of LBW, preterm birth, and becoming underweight among HEU infants, specifically male infants. In contrast to the impact of maternal pregnancy-IPT on infant growth, infant IPT administration among HEU infants did not significantly impact growth outcomes in the first two years of life. TB-HIV co-treatment did not affect viral suppression and CD4 reconstitution post-ART among young hospitalized children initiating ART, suggesting tolerability and lack of interference of TB treatment on ART levels. TB-ART-treated CHIV had more rapid growth reconstitution, despite which growth deficits persisted, suggesting the need for growth monitoring and management in co-treated CHIV. The findings inform strategies to optimize TB-HIV co-treatment in CHIV, provide additional evidence regarding maternal and infant IPT and safety in infancy, and inform clinical care for CHIV and HEU children.