"Maternal HIV Status & Risk of Infant mTB Infection as Measured by Tuberculin Skin Test"
Find full article: Maternal HIV Status and Risk of Infant Mycobacterium tuberculosis Infection as Measured by Tuberculin Skin Test - PubMed (nih.gov)
Background:
The effect of maternal HIV on infant Mycobacterium tuberculosis (Mtb) infection risk is not well-characterized.
Methods:
Pregnant women with/without HIV and their infants were enrolled in a longitudinal cohort in Kenya. Mothers had interferon gamma-release assays (QFT-Plus) and tuberculin skin tests (TST) at enrollment in pregnancy; children underwent TST at 12 and 24 months of age. We estimated the incidence and correlates of infant TST-positivity using Cox proportional hazards regression.
Results:
Among 322 infants, 170 (53%) were HIV-exposed and 152 (47%) were HIV-unexposed. Median enrollment age was 6.6 weeks [interquartile range (IQR): 6.1–10.0]; most received Bacillus Calmette-Guerin (320, 99%). Thirty-nine (12%) mothers were TST-positive; 102 (32%) were QFT-Plus-positive. Among HIV-exposed infants, 154 (95%) received antiretrovirals for HIV prevention and 141 (83%) of their mothers ever received isoniazid preventive therapy (IPT). Cumulative 24-month infant Mtb infection incidence was 3.6/100 person-years (PY) [95% confidence interval (CI): 2.4–5.5/100 PY]; 5.4/100 PY in HIV-exposed infants (10%, 17/170) versus 1.7/100 PY in HIV-unexposed infants (3.3%, 5/152) [hazard ratio (HR): 3.1 (95% CI: 1.2–8.5)]. More TST conversions occurred in the first versus second year of life [5.8 vs. 2.0/100 PY; HR: 2.9 (95% CI: 1.0–10.1)]. Infant TST-positivity was associated with maternal TST-positivity [HR: 2.9 (95% CI: 1.1–7.4)], but not QFT-Plus-positivity. Among HIV-exposed children, Mtb infection incidence was similar regardless of maternal IPT.
Conclusions:
Mtb infection incidence (by TST) by 24 months of age was ~3-fold higher among HIV-exposed children, despite high maternal IPT uptake. Overall, more TST conversions occurred in the first 12 months compared to 12–24 months of age, similar in both HIV-exposed and HIV-unexposed children.
Millions of children are exposed to Mycobacterium tuberculosis (Mtb) every year.1 Early Mtb infection identification in young children is important, due to the substantially increased risk of developing tuberculosis (TB) within 1–2 years following infection without intervention, which is approximately 20% among children under 5 years of age.2 Children born to mothers with HIV may be predisposed to early Mtb infection due to increased TB exposure.3–5 HIV-exposed children may be more immunologically vulnerable as a result of HIV exposure in utero and potentially reduced cellular response to Bacillus Calmette-Guerin (BCG) vaccination.3,6–8
Previous estimates of Mtb infection among HIV-exposed infants have been primarily prior to universal maternal antiretroviral therapy (ART).3,4,9,10 Whether maternal HIV increases susceptibility to infant Mtb infection under contemporary conditions of widespread maternal ART and programmatic isoniazid preventive therapy (IPT) is unknown.
We conducted a prospective longitudinal cohort study of children with and without HIV exposure, enrolled at 6 weeks of age and serially tested for Mtb infection at 12 and 24 months of age measured by tuberculin skin test (TST). For this analysis, we estimated cumulative infant Mtb infection incidence overall and by HIV exposure, compared incidence of Mtb infection between the first and second year of life, and assessed correlates of infant Mtb infection.
MATERIALS AND METHODS
Study Design and Participants
We conducted an observational cohort study where we enrolled pregnant women with and without HIV and followed them and their infants longitudinally for 24 months. This study took place at 4 public antenatal clinics in western Kenya, where maternal HIV prevalence is 14%–21%.11 Women were eligible for enrollment if they were pregnant between 20 and 34 weeks gestation, ≥16 years of age and did not have active TB in the past 1 year.
Study Procedures
Women completed the enrollment visit prior to birth and then attended up to 5 follow-up visits at 6 weeks, 6, 12, 18 and 24 months following infant birth. At all study visits, women completed questionnaires that captured information on demographics, maternal HIV history, IPT use, infant growth and household characteristics, TB symptoms and exposure. Women were tested for Mtb infection using interferon gamma-release assays (IGRA, QFT-Plus) and a TST at enrollment. At 12 and 24 months, we tested infants for Mtb infection using a TST. For participants with HIV, a TST induration ≥5 mm was considered positive; for participants without HIV, an induration ≥10 mm was considered positive, per routine clinical cutoff guidelines.12,13 Description of parent cohort design, and baseline maternal characteristics and results of baseline maternal QFT-Plus and TST testing in pregnancy have been previously reported.14
At the time of study implementation, Kenyan national guidelines recommended a 6-month course of IPT for persons with HIV including pregnant women.15 Women with HIV and infants found to have positive TST (and/or QFT-Plus for mothers) as well as participants with reported TB exposure during the study were referred for IPT evaluation if they had not already received IPT. At the time, HIV-negative adults were not included in the national TB prevention guidelines.15
Outcomes
Our primary outcome was cumulative infant Mtb infection incidence by 24 months of age as measured by TST, overall and by HIV exposure, with any positive TST (either at 12 or 24 months) considered “ever positive.” Additionally, we compared the incidence of Mtb infection between the first and second year of life and correlates of cumulative Mtb infection overall and stratified by HIV exposure.
Statistical Analysis
Maternal and infant baseline characteristics were described using proportions for categorical variables and medians and interquartile ranges for continuous variables. Baseline characteristics were compared between children with and without HIV exposure using a generalized linear model with a log link and Poisson family. For children found to have a positive TST, the timing of Mtb infection was estimated to have occurred mid-way between birth or the last negative test and the first positive test. Children with only negative TSTs were censored at the time of their last negative TST. Cox proportional hazards regression models were used to estimate hazard ratios (HR) of cumulative Mtb infection incidence by HIV exposure, comparing 12-month to 12–24-month Mtb infection incidence, and to assess correlates of cumulative 24-month infant Mtb infection as measured by TST. Covariates of cumulative infant Mtb infection with P < 0.05 in univariate models were included in multivariate analyses using Cox proportional hazards regression models. For children with TST results at both time points, TST conversions [negative (<10 mm) to positive (≥10 mm)] and reversions (positive to negative) were calculated and compared by infant HIV exposure with a 2-sample Wilcoxon signed-rank test of proportions. We also conducted sensitivity analyses using a TST ≥5 mm induration cutoff for all participants irrespective of HIV status, as well as a sensitivity analysis on reversions, with TST reversions defined as repeat TST ≤5 mm with ≥3 mm decrease from conversions.16
All estimates were reported using 95% confidence intervals (CI), and all statistical tests were 2-sided with α of 0.05. Analyses were performed using Stata version 15 (StataCorp LP, College Station, TX).
Ethics Statement
This study was approved by the Kenyatta National Hospital-University of Nairobi Ethics and Research Committee, the University of Washington Institutional Review Board and Jaramogi Oginga Odinga Teaching and Referral Ethics Committee.
RESULTS
Participant Characteristics
From January 2018 to December 2019, we enrolled 400 pregnant women (200 with and 200 without HIV). Three hundred fifty-five infants (184 HIV-exposed and 171 HIV-unexposed) were enrolled at a median of 6.6 weeks of age [interquartile range (IQR): 6.1–10.0] (Fig. 1). Among 322 infants with available TST results at 12 and/or 24 months of age, 170 (53%) were HIV-exposed and 152 (47%) were HIV-unexposed, 164 (51%) were female and 320 (99%) received BCG at birth.
Infant Mtb Infection Incidence (as Measured by TST) and Correlates
Overall, 6.8% (22/322) of infants had a positive TST by 24 months. Cumulative infant Mtb infection incidence by 24 months was 3.6/100 person-years (PY) (95% CI: 2.4–5.5/100 PY); 5.4/100 PY in HIV-exposed infants (10%, 17/170) versus 1.7/100 PY in HIV-unexposed infants (3.3%, 5/152) [HR: 3.1 (95% CI: 1.2–8.5); P = 0.024] (Fig. 2, Table 2). In sensitivity analysis, using a TST ≥5 mm induration irrespective of HIV status, cumulative infant Mtb infection incidence by 24 months was 14.7/100 PY (95% CI: 11.8–18.3/100 PY); 18.8/100 PY in HIV-exposed infants (30.6%, 52/170) versus 10.6/100 PY in HIV-unexposed infants (19.1%, 29/152) [HR: 1.8 (95% CI: 1.1–2.8); P = 0.012] (Table, Supplemental Digital Content 1, https://links.lww.com/INF/F312).
Most infant TST conversions occurred in the first versus second year of life [5.8 vs. 2.0/100 PY; HR: 2.9 (95% CI: 1.0–10.1); P = 0.03], with a similar pattern for both HIV-exposed and unexposed infants (Table 3). Among HIV-exposed infants, Mtb infection incidence was similar regardless of maternal history of IPT use [maternal IPT 4.5 vs. no IPT 6.4/100 PY; HR: 0.7 (95% CI: 0.3–1.8); P = 0.47].
Cumulative infant Mtb infection was associated with maternal HIV-positive status [HR: 3.1 (95% CI: 1.2–8.5); P = 0.02] and maternal TST positivity in pregnancy, both when using HIV-specific TST cutoffs [HR: 2.9 (95% CI: 1.1–7.4); P = 0.03], and 10 mm TST cutoff for mothers [HR: 4.7 (95% CI: 2.0–10.8); P ≤ 0.001]. However, infant Mtb infection was not associated with maternal QFT-Plus positivity (Table 4). After adjusting for maternal HIV status and maternal TST positivity, the association of infant Mtb infection with maternal TST ≥10 mm [aHR: 4.5 (95% CI: 1.9–10.3); P ≤ 0.001] and maternal HIV status [aHR: 3.0 (95% CI: 1.09–8.02); P ≤ 0.03] remained statistically significant (maternal TST positivity by clinical cutoffs by HIV status not included in the model). Among HIV-exposed infants, living in a single-room household [HR: 3.0 (95% CI: 1.1–8.0); P = 0.03] was associated with an increased risk of infant Mtb infection, while older maternal age [HR: 0.9 (95% CI: 0.8–0.9); P = 0.02] and higher maternal BMI [HR: 0.8 (95% CI: 0.7–0.9); P = 0.02] were associated with decreased risk of infant Mtb infection (Table, Supplemental Digital Content 2, https://links.lww.com/INF/F313). There was also a trend for decreased likelihood of infant Mtb infection among HIV-exposed infants who had higher weight-for-age Z score [HR: 0.6 (95% CI: 0.3–1.0); P = 0.06] and for infants whose mothers’ received ART prior to pregnancy [HR: 0.4 (95% CI: 0.2–1.1); P = 0.06] though not statistically significant.
One mother with HIV was diagnosed with TB at 6 weeks postpartum and was initiated on TB treatment. However, her child was TST negative at both timepoints. One child from the HIV-unexposed group with a positive TST at 12 months without reported household TB exposure was diagnosed with TB at 24 months of age and initiated TB treatment.
Infant TST Conversions and Reversions
Among 281 children who had TST results at both 12 and 24 months, 1.8% remained persistently positive, 1.8% converted from negative to positive, and 3.9% reverted from positive to negative. Proportions of TST conversion and reversion were significantly higher among HIV-exposed compared to HIV-unexposed children (conversion: 2.6% vs. 0.8%, P = 0.005; reversion: 5.9% vs. 1.6%, P < 0.0001 respectively) (Figure, Supplemental Digital Content 3, https://links.lww.com/INF/F314). Restricting the analysis to TST-positive participants at 12 months with subsequent 24-month assessment, HIV-exposed children still had more frequent reversions than HIV-unexposed children [9/12 (75.0%) vs. 2/4 (50.0%), P = 0.35], but this difference was not statistically significant. In sensitivity analyses with reversion defined as repeat TST ≤5 mm with ≥3 mm decrease from conversions,16 a smaller proportion of children [8 (2.9%)] reverted from positive to negative, with 6 (3.9%) among HIV-exposed children and 2 (1.7%) among HIV-unexposed children. HIV-exposed children still had more frequent reversions compared to HIV-unexposed children [6/8 (75.0%) vs. 2/4 (50.0%), P ≤ 0.001].
DISCUSSION
In this longitudinal analysis of HIV-exposed and HIV-unexposed children in a high TB burden setting in western Kenya, infant Mtb infection incidence by 24 months of age as measured by TST was 3.6/100 person-years and 3-fold higher among HIV-exposed compared to HIV-unexposed children (5.4 vs. 1.7/100 PY), despite high levels of maternal programmatic IPT and universal maternal ART. The risk of TST conversions was almost 3-fold higher in the first year of life compared to the second year with a similar pattern for both HIV-exposed and HIV-unexposed children. Infant Mtb infection was associated with maternal TST positivity in pregnancy using clinical cutoffs and induration of ≥10 mm regardless of HIV status but not maternal QFT-Plus. Among HIV-exposed children, living in a singleroom household was associated with increased risk, while older maternal age and higher maternal BMI were associated with decreased risk of infant Mtb infection.
This is a unique study that compares Mtb infection rates in HIV-exposed and HIV-unexposed children enrolled at 6 weeks of age and followed longitudinally to 24 months of age. Children in HIV/TB endemic areas are at high risk of Mtb infection, which can quickly progress to TB disease due to their developing immunity.4,8,14,15 A systematic review and meta-analysis estimated a 20% TB risk for young children within 2 years of exposure, with the majority of children under 5 years developing TB disease within a few months of exposure.2 Our findings are consistent with those of a randomized clinical trial conducted in western Kenya, assessing the efficacy of isoniazid in HIV-exposed infants to prevent primary Mtb infection, in which the majority of TST conversions occurring in the first year of life (8.6/100 PY), though cumulative Mtb infection incidence was lower in this cohort study (3.6/100 PY), which enrolled both HIV-exposed and unexposed infants.17,18 A cross-sectional study conducted in Uganda assessing the age-specific prevalence of TB infection under 5 years and the association between HIV exposure found 24% TST positivity among children ≤60 months of age with the highest prevalence of TST positivity among children occurring in their first year (36%). The Ugandan study also identified HIV-exposed children as a high-risk population for TB infection with a 2.4 higher odds of TST and QFT test positivity compared with HIV-unexposed children.9 A prospective birth cohort study conducted in South Africa found a similar trend in higher rates of TST conversions occurring in the first year of life, 16.5/100 PY (compared to 5.1/100 PY between 1 and 2 years), in which 22% of mothers had HIV and maternal IPT use was not reported.19 The higher incidence of TST-positivity in the first year of life may be attributable to young children’s heightened vulnerability to Mtb infection following exposure, though cross-reactivity to BCG may play a role in influencing TST positivity.2 This is congruent with findings from prechemotherapy natural history research, which found that infants under 1 year of age had the highest risk of acquiring TB following exposure.
In our study, cumulative 24-month Mtb infection incidence in HIV-exposed children was 3-fold higher compared to HIV-unexposed children. Some studies have found that HIV-exposed children have higher rates of morbidity and mortality than HIV-unexposed children, including high rates of Mtb infection, even if they do not acquire HIV.4,20 This observation could be attributed to a variety of factors, including social considerations and immunological differences, some of which have been shown to persist into childhood.7,21 HIV-exposed children have high exposure to TB and may be more immunologically vulnerable due to HIV exposure in utero.7 Our estimates indicate that children under the age of 5 years, especially HIV-exposed children are at substantial risk of developing Mtb infection with a potential of progressing to active TB and must be prioritized by developing new prevention and early case finding strategies.
The study also identified key risk factors associated with infant Mtb infection including maternal HIV and maternal TST positivity. Living in a single household and having more household members were both associated with a positive TST among HIV-exposed children. Transmission risk may be higher with more household members, especially in settings with limited ventilation. Increased exposure raises the risk of Mtb infection among HIV-exposed children, especially in households where there is close or prolonged contact. The observed TST conversions could have been attributed to the potential cumulative higher TB exposure within the household or outside household exposure to persons with undiagnosed TB or subclinical TB. Older maternal age and higher maternal BMI were associated with a decreased risk of infant Mtb infection among HIV-exposed children. There was a trend for HIV-exposed children with higher weight-for-age Z scores and those whose mothers initiated ART prior to pregnancy were less likely to have a positive TST, though neither were statistically significant.
The proportions of TST reversions and conversions were higher particularly among HIV-exposed children compared to HIV-unexposed children. Even after restricting our analysis to TST-positive participants at 12 months with subsequent 24-month assessment, HIV-exposed children still had more frequent reversions than HIV-unexposed children. Children under the age of 1 year have an immature immune system; their ability to mount a robust immune response may not be fully developed, leading to less reliable or weaker responses to TST resulting in reversions. HIV-exposed children are more likely to have been exposed to TB. As the immune response fluctuates, the higher prevalence of Mtb infection in these children may have contributed to a higher number of subsequent TST reversions. There is a potential of BCG cross-reactivity with TST, which may have caused a positive result that waned over time, resulting in reversions.
This study had some strengths: we had a retention rate of 91% despite the COVID-19 pandemic and national health workers strike experienced in Kenya, and our data reflects the risk of infant Mtb infection in the setting of contemporary universal ART and high programmatic IPT use in people with HIV. Our analysis also had limitations: we relied on TST, an imperfect measure of Mtb infection with a potential of BCG cross-reactivity; this will be addressed in the future by the peripheral blood mononuclear cells (PBMC) collected for use in flow analysis, targeting Mtb-specific markers.7,8 There was a differential follow-up between HIV-exposed and HIV-unexposed children. Follow-up occurred during routine visits per Kenyan guidelines, which were less disrupted in HIV prevention of maternal-to-child transmission settings compared to routine pediatric care during the COVID-19 pandemic.
In conclusion, the risk of Mtb infection is substantial in HIV-exposed children in high TB burden regions, particularly during the first year of life. With the successful prevention of maternal-to-child transmission of HIV programs, the population of HIV-exposed but uninfected children is growing. Long-term interventions including early Mtb infection identification targeting HIV-exposed children during their childhood are essential.
ACKNOWLEDGMENTS
The authors acknowledge the MITIPS study staff, county directors of health for both Kisumu and Siaya, health facility staff, University of Washington (UW)-Kenya and Kenyatta National Hospital Research and Programs operational staff. We thank Qiagen for providing discounted QFT-Plus test kits and the Kenya Medical Research Institute (KEMRI)/Centers for Disease Control and Prevention (CDC) in Kisumu, Kenya, for performing the QFT-Plus assays. Above all, our sincere thanks to the study participants and their families.
REFERENCES
1. Dodd PJ, Gardiner E, Coghlan R, et al. Burden of childhood tuberculosis in 22 high-burden countries: a mathematical modelling study. Lancet Glob Health. 2014;2:e453–e459.
2. Martinez L, Cords O, Horsburgh CR, et al. The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis. Lancet. 2020;395:973–984.
