Abstract
Background
The effect of maternal HIV on infant M. 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 (IGRA, QFT-Plus) and tuberculin skin tests (TST) at enrollment in pregnancy; children underwent TST at 12 and 24 months of age. We estimated 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 (IQR 6.1–10.0); most received BCG (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 PY (95%CI 2.4–5.5/100 PY); 5.4/100 PY in HIV-exposed infants (10%, 17/170) vs. 1.7/100 PY in HIV-unexposed infants (3.3%, 5/152) (HR 3.1 [95%CI 1.2–8.5]). More TST conversions occurred in the 1st vs. 2nd 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.
Keywords: M. tuberculosis infection, HIV-exposed children, HIV-unexposed children, tuberculin skin test, isoniazid
INTRODUCTION
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 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 1st and 2nd year of life, and assessed correlates of infant Mtb infection.
MATERIALS AND METHODS
Study Design & 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 four public antenatal clinics in western Kenya, where maternal HIV prevalence is 14–21% (11). Women were eligible for enrollment if they were pregnant between 20–34 weeks gestation, ≥16 years of age, and did not have active TB in the past one year.
Study Procedures
Women completed the enrollment visit prior to birth, and then attended up to five follow-up visits at 6 weeks, 6 months, 12 months, 18 months, 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 an interferon gamma-release assays (IGRA, QFT-Plus) and a tuberculin skin test (TST) at enrollment. At 12 and 24 months, we tested infants for Mtb infection using a TST. For participants with HIV, an 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 six-month course of IPT for persons with HIV including pregnant women (15). Women with HIV and HIV-exposed 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 incidence of Mtb infection between the 1st and 2nd 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 log link and Poisson family. For children found to have a positive TST, timing of Mtb infection was estimated to have occurred mid-way between birth or last negative test and 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 months 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-values less than 0.05 in univariate models were included in multivariate analyses using Cox proportional hazards regression models. For children with TST results at both timepoints, TST conversions (negative [<10 mm] to positive [≥10 mm]) and reversions (positive to negative) were calculated and compared by infant HIV exposure with a two-sample Wilcoxon signed-rank test of proportions. We also conducted sensitivity analyses using a TST ≥5 mm induration cut-off 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, and all statistical tests were two sided with α of 0.05. Analyses were performed using Stata version 15 (StataCorp LP, College Station, TX, USA).
Ethics Statement
This study was approved by the Kenyatta National Hospital-University of Nairobi Ethics and Research Committee, 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 (IQR 6.1–10.0) (Figure 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.
Figure 1:
Study flow of infants with and without HIV exposure evaluated for Mtb infection by TST up to 24 months of age.
Among 170 HIV-exposed infants, 154 (95%) received ART for HIV prevention. All mothers with HIV were on ART at enrollment in pregnancy (including 114 [67.1%] who initiated ART prior to this pregnancy); 141 (82.9%) had ever received IPT, of whom 32 (22.7%) were on IPT at enrollment. This analysis includes two infants with new HIV diagnosis confirmed at 6 weeks of age and 6 months of age, respectively.
Infants with HIV-exposure were more likely to have mothers who were older (median age 28 vs. 23 years) and live in more crowded conditions (single room households and more household members) compared with HIV-unexposed infants (Table 1). HIV-unexposed infants were more likely to live in a household which lacked flush toilets. Two infants from the HIV-exposed group had a reported household TB exposure during the study.
Table 1.
Infant and maternal characteristics
| Baseline characteristics | HIV-exposed N=170 n (%) or median (IQR) | HIV-unexposed N=152** n (%) or median (IQR) | RR* (95% CI) | p |
|---|---|---|---|---|
|
| ||||
| Infant characteristics | ||||
| Female sex | 90 (52.9) | 74 (48.7) | 0.92 (0.75–1.13) | 0.447 |
| Age, weeks | 6.4 (6.1–10.0) | 6.9 (6.1–10.1) | 0.99 (0.98–1.00) | 0.483 |
| WAZ score (N=308) | −0.1 (−1.1–0.6) | −0.1 (−0.6–0.8) | 0.92 (0.85–1.00) | 0.053 |
| Underweight (WAZ < −2) (N=308) | 6 (3.7) | 6 (4.2) | 0.94 (0.53–1.67) | 0.824 |
| BCG vaccination | 168 (98.8) | 152 (100) | -- | 0.500¶ |
| Received ARVs for PMTCT (N=163) | 154 (94.5) | -- | -- | -- |
| Maternal characteristics | ||||
| Age, years | 28 (24–31) | 23 (21–26.5) | 1.05 (1.04–1.07) | <0.001 |
| BMI, kg/m2 | 24.4 (22.3–27.9) | 23.8 (22.2–27.5) | 1.01 (0.99–1.04) | 0.240 |
| Partner with HIV (N=255) | 61 (45.5) | -- | -- | -- |
| HIV viral load undetectable† (N=148) | 102 (68.9) | -- | -- | -- |
| CD4, cells/mm3† (N=76) | 456 (330–654) | -- | -- | -- |
| ART before pregnancy (N=170) | 114 (67.1) | -- | -- | -- |
| ART on enrollment (N=170) | 170 (100) | -- | -- | -- |
| Any IPT use (N=170) | 141 (82.9) | -- | -- | -- |
| IPT on enrollment (N=141) | 32 (22.7) | -- | -- | -- |
| LTBI+ (TST+ or QFT-Plus+)‡ | 61 (35.9) | 54 (35.5) | 1.00 (0.81–1.25) | 0.947 |
| QFT-Plus+ (N=321) | 51 (30.0) | 51 (33.8) | 0.92 (0.73–1.16) | 0.477 |
| TST+ (N=321) ‡ | 33 (19.4) | 6 (4.0) | 1.74 (1.45–2.08) | <0.001 |
| TST ≥10 mm (N=321) | 17 (10.0) | 6 (4.0) | 1.44 (1.10–1.88) | 0.008 |
| TST ≥5 mm (N=321) | 33 (19.4) | 21 (13.9) | 1.19 (0.93–1.52) | 0.159 |
| Household characteristics | ||||
| Household TB exposure during study | 2 (1.18) | -- | -- | -- |
| Lack of running water | 98 (57.8) | 77 (50.7) | 1.14 (0.93–1.41) | 0.214 |
| Lack of electricity | 54 (31.8) | 58 (38.2) | 0.87 (0.69–1.10) | 0.242 |
| Lack of flush toilet | 161 (94.7) | 149 (98.0) | 0.69 (0.49–0.98) | 0.036 |
| Persons in household | 4 (3–5) | 3 (2–4) | 1.07 (1.01–1.14) | 0.030 |
| Single room household | 28 (16.5) | 41 (27.0) | 0.72 (0.53–0.98) | 0.038 |
Abbreviations: IQR interquartile range, WAZ weight-for-age Z score, ARV antiretrovirals, HIV human immunodeficiency virus, TB tuberculosis, IPT isoniazid preventive therapy, TST tuberculin skin test, LTBI Latent tuberculosis infection, QFT-Plus QuantiFERON-TB Gold, PMTCT Prevention of Mother to Child Transmission, BCG Bacillus Calmette-Guerin
Includes 2 children with new HIV diagnoses at 6 weeks of age and 6 months of age
Relative risk (RR) estimated using a generalized linear model (GLM) with log link and Poisson family
CD4 and HIV viral load data collected from routine programmatic data. Undetectable viral load ≤20 copies/ml
TST positive defined as 5 mm induration if HIV positive and 10 mm induration if HIV negative
Fisher’s exact p-value
Infant Mtb infection incidence (as measured by TST) and correlates.
Overall, 6.8% (22/322) infants had a positive TST by 24 months. Cumulative infant Mtb infection incidence by 24 months was 3.6/100 PY (95%CI 2.4–5.5/100 PY); 5.4/100 PY in HIV-exposed infants (10%, 17/170) vs. 1.7/100 PY in HIV-unexposed infants (3.3%, 5/152) (HR 3.1 [95%CI 1.2–8.5], p=0.024) (Figure 2, Table 2a). In sensitivity analysis, using a TST ≥5mm 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) vs. 10.6/100 PY in HIV-unexposed infants (19.1%, 29/152) (HR 1.8 [95%CI 1.1–2.8], p=0.012) (Supplemental Digital Content 1, Table).
Figure 2.
Incidence of M. tuberculosis infection among children with and without HIV as measured by TST. M. tuberculosis infection incidence at 12-months, 12–24 months, and cumulative 24-months among children with at least one TST performed.
Table 2a.
Mtb infection incidence rates comparison between children with and without HIV exposure
| N | n (%)† | Rate per 100 PY (95% CI) | HR* (95% CI) | p | |
|---|---|---|---|---|---|
|
| |||||
| 12 month incidence | 298 | 17 (5.7) | 5.8 (3.6–9.4) | ||
| HIV Exposure¶ | 165 | 13 (7.9) | 8.1 (4.7–14.0) | 2.70 (0.87–8.21) | 0.085 |
| No HIV exposure | 133 | 4 (3.0) | 3.0 (1.1–8.1) | ref | -- |
|
| |||||
| 12–24 month incidence | 265 | 5 (1.9) | 2.0 (0.8–4.8) | ||
| HIV Exposure¶ | 141 | 4 (2.8) | 3.1 (1.1–8.2) | 3.58 (0.40–32.1) | 0.254 |
| No HIV exposure | 124 | 1 (0.8) | 0.8 (0.1–5.9) | ref | -- |
|
| |||||
| Cumulative 24-months incidence | 322 | 22 (6.8) | 3.6 (2.4–5.5) | ||
| HIV Exposure¶ | 170 | 17 (10.0) | 5.4 (3.4–8.7) | 3.10 (1.16–8.54) | 0.024 |
| No HIV exposure | 152 | 5 (3.3) | 1.7 (0.7–4.1) | ref | -- |
n/N
Hazard ratio (HR) estimated using Cox proportional hazards regression
Includes 2 children with new HIV diagnosis at 6 weeks and 6 months of age
Most infant TST conversions occurred in the 1st vs. 2nd 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 2b). Among HIV-exposed infants, Mtb infection incidence was similar regardless of maternal history of IPT use (maternal IPT 4.5 vs. no IPT 6.4/100PY, HR 0.7 [95%CI 0.3–1.8], p=0.47).
Table 2b.
Mtb infection incidence rates comparison between 12 month and 12-24 months of life
| N | n (%)† | Rate per 100 PY (95% CI) | HR* (95% CI) | p | |
|---|---|---|---|---|---|
|
| |||||
| Overall | |||||
| 12-month incidence | 298 | 17 (5.7) | 5.8 (3.6–9.4) | 2.92 (1.03–10.13) | 0.029 |
| 12–24 month incidence | 265 | 5 (1.9) | 2.0 (0.8–4.8) | ref | -- |
|
| |||||
| HIV Exposure | |||||
| 12 months incidence¶ | 165 | 13 (7.9) | 8.1 (4.7–14.0) | 2.65 (0.82–11.17) | 0.079 |
| 12–24 month incidence | 141 | 4 (2.8) | 3.1 (1.1–8.2) | ref | -- |
|
| |||||
| No HIV exposure | |||||
| 12 month incidence¶ | 133 | 4 (3.0) | 3.0 (1.1–8.1) | 3.65 (0.36–179.75) | 0.257 |
| 12–24 month incidence | 124 | 1 (0.8) | 0.8 (0.1–5.9) | ref | -- |
n/N
Hazard ratio (HR) estimated using Cox proportional hazards regression
Includes 2 children with new HIV diagnosis at 6 weeks and 6 months of age.
Cumulative infant Mtb infection was associated with maternal HIV 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 cut-offs (HR 2.9 [95%CI 1.1–7.4], p=0.03), and 10 mm TST cut-off 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 3). 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 cut-offs by HIV-status not included in 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 (Supplemental Digital Content 2, Table). There was also a trend in increased likelihood of infant Mtb infection among HIV-exposed infants who had lower weight for age z-score (HR 0.6 [95%CI 0.3–1.0], p=0.06) and a decreased likelihood of Mtb infection 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.
Table 3.
Correlates of cumulative infant TST positivity up to 24 months
| Baseline characteristics | TST positive‡ N=22 n (%) or median (IQR) | TST negative N=300 n (%) or median (IQR) | HR* (95% CI) | p | aHRΪ | p |
|---|---|---|---|---|---|---|
|
| ||||||
| Infant characteristics | ||||||
| Female sex | 9 (40.9) | 155 (51.7) | 0.65 (0.28–1.52) | 0.317 | -- | |
| HIV exposure | 17 (77.3) | 153 (51.0) | 3.14 (1.16–8.52) | 0.024 | 2.96 (1.09–8.02) | 0.033 |
| Age, wks | 6.1 (6.0–6.7) | 6.6 (6.1–10.1) | 0.80 (0.63–1.02) | 0.067 | -- | |
| WAZ score (N=308) | −0.1 (−1.4– 0.4) | 0.04 (−0.8–0.7) | 0.82 (0.52–1.27) | 0.374 | -- | |
| Underweight (WAZ< −2) (N=308) | 1 (4.6) | 11 (3.9) | 1.17 (0.16–8.70) | 0.878 | -- | |
| BCG vaccination | 22 (100) | 298 (99.3) | -- | 1.00¶ | -- | |
| Received ARVs for PMTCT | 16 (94.1) | 138 (94.5) | -- | 1.00¶ | -- | |
| Maternal characteristics | ||||||
| Age, years | 23.5 (20–30) | 25 (22–29) | 0.97 (0.89–1.05) | 0.489 | -- | |
| BMI, kg/m2 | 24.0 (22.5–25.7) | 24.1 (22.2–27.7) | 0.93 (0.82–1.04) | 0.207 | -- | |
| Partner with HIV (N=255) | 6 (28.6) | 55 (23.5) | 1.30 (0.50–3.34) | 0.590 | -- | |
| HIV viral load undetectable (N=148)† | 9 (60.0) | 93 (69.9) | 0.69 (0.25–1.94) | 0.485 | -- | |
| CD4, cells/mm3† (N=76) | 492.5 (410.5–593.5) | 454.5 (320–688) | 1.00 (1.00–1.00) | 0.976 | -- | |
| ART before pregnancy (N=170) | 8 (47.1) | 106 (69.3) | 0.41 (0.16–1.06) | 0.066 | -- | |
| ART on enrollment (N=170) | 17 (100.0) | 153 (100.0) | 1 | n/a | -- | |
| Any IPT use (N=170) | 15 (88.2) | 126 (82.4) | 1.63 (0.37–7.14) | 0.515 | -- | |
| IPT on enrollment (N=141) | 4 (26.7) | 28 (22.2) | 1.29 (0.41–4.05) | 0.662 | -- | |
| LTBI+ (TST+ or QFT-Plus+)‡ | 11 (50.0) | 104 (34.8) | 1.21 (0.53–2.80) | 0.650 | -- | |
| QFT-Plus + (N=321) | 10 (45.5) | 92 (30.8) | 1.15 (0.50–2.67) | 0.740 | -- | |
| TST+ (N=321)‡ | 6 (27.3) | 33 (11.0) | 2.90 (1.14–7.42) | 0.026 | -- | |
| TST ≥10 mm (N=321) | 5 (22.7) | 18 (6.0) | 4.70 (2.03–10.83) | <0.001 | 4.48 (1.94–10.35) | <0.001 |
| TST ≥5 mm (N=321) | 6 (27.3) | 48 (16.1) | 2.41 (0.94–6.16) | 0.066 | -- | |
| Household characteristics | ||||||
| Household TB exposure during study | -- | 2 (0.67) | -- | -- | -- | -- |
| Lack of running water | 13 (59.1) | 162 (54.0) | 1.20 (0.52–2.82) | 0.662 | -- | |
| Lack of electricity | 6 (27.3) | 106 (35.3) | 0.68 (0.27–1.75) | 0.418 | -- | |
| Lack of flush toilet | 22 (100) | 288 (96.0) | 1 | n/a | ||
| Persons in household | 3 (3–5) | 3 (3–5) | 0.97 (0.74–1.29) | 0.855 | -- | |
| Single room household | 6 (27.3) | 63 (21.0) | 1.39 (0.54–3.55) | 0.493 | -- | |
Abbreviations: IQR interquartile range, WAZ weight-for-age Z score, ARV antiretrovirals, HIV human immunodeficiency virus, TB tuberculosis, IPT isoniazid preventive therapy, TST tuberculin skin test, LTBI Latent tuberculosis infection, QFT-Plus QuantiFERON-TB Gold.
Hazard ratio(HR) estimated using cox proportional hazard regression. ΪAdjusted for infant HIV exposure status and maternal TST ≥10 mm
CD4 and HIV viral load data collected from routine programmatic data. Undetectable viral load ≤20 copies/ml.
TST positive defined as ≥5 mm induration if HIV positive and ≥10 mm induration if HIV negative.
Fisher’s exact p-value
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 on TB treatment.
Infant TST conversions and reversions
Among 281 children who had TST result at both 12 and 24 months, 1.8% (5) remained persistently positive, 1.8% (5) converted from negative to positive, and 3.9% (11) 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) (Supplemental Digital Content 3, figure). Restricting 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 person-years), despite high levels of maternal programmatic IPT and universal maternal ART. The risk of TST conversions was almost 3-fold higher in the 1st year of life compared to the 2nd 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 cut offs and induration of ≥10mm regardless of HIV status but not maternal QFT-plus. Among HIV-exposed children, living in a one room 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 were 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 TST conversions occurring in the first year of life 16.5/100PY (compared to 5.1/100 PY between 1–2 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 pre-chemotherapy natural history research, which found that infants under one year of age had the highest risk of acquiring TB following exposure, with the risk reducing over time.
In our study, Mtb infection incidence in HIV-exposed children was 3-fold higher compared to HIV unexposed children, reaching statistical significance at 24 months. 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 status 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 a close or prolonged contact. The observed TST conversions could have been attributed to the cumulative higher TB exposure within the household or outside household member with undiagnosed TB or subclinical TB. Older maternal age and higher maternal BMI were associated with decreased risk of infant Mtb infection among HIV-exposed children. There was a trend for HIV-exposed children with lower weight for age z-score to have a positive TST, while infants 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 to reversions. HIV-exposed children are more likely to have been exposed to TB. As the immune response fluctuates, the higher prevalence of TBI in these children may have contributed to a higher number of TST reversions. There was 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 risk in the setting of contemporary universal ART and high programmatic IPT use in people with HIV. Our analysis also had weaknesses: we relied on TST an imperfect measure of Mtb infection with a potential of BCG cross-reactivity, this will be addressed in future by the PBMCs collected which will be used in flow analysis, targeting specific TB markers (7,8). There was a differential follow-up between HIV-exposed and HIV-unexposed children. Follow-up occurred during routine Kenyan guidelines, which was 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 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.
Supplementary Material
ACKNOWLEDGEMENTS
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.
FUNDING
The National Institute of Allergy and Infectious Diseases (NIAID), the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Center for Advancing Translational Sciences at the National Institutes of Health funded this research (grant numbers NIH/NIAID K23AI120793 to S.M.L.; NIH/NIAID R01AI142647 to G.J.-S.; NIH/NICHD R21HD098746 to S.M.L.; and NIH UL1TR000423 for REDCap).
Footnotes
CONFLICTS OF INTEREST: The authors report no conflicts of interest.
Preliminary data was presented at the 2022 Conference on Retroviruses and Opportunistic Infections (CROI), February 12-16, 2022, and the 24th International AIDS Conference AIDS 2022, July 29-August 2, 2022.
REFERENCES
- 1.Dodd PJ, Gardiner E, Coghlan R, Seddon JA. Burden of childhood tuberculosis in 22 high-burden countries: a mathematical modelling study. Lancet Glob Health. 2014. Aug 1;2(8):e453–9. [DOI] [PubMed] [Google Scholar]
- 2.Martinez L, Cords O, Horsburgh CR, Andrews JR, Acuna-Villaorduna C, Desai Ahuja S, et al. The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis. The Lancet. 2020. Mar 21;395(10228):973–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Cotton MF, Schaaf HS, Lottering G, Weber HL, Coetzee J, Nachman S, et al. Tuberculosis exposure in HIV-exposed infants in a high-prevalence setting. Int J Tuberc Lung Dis Off J Int Union Tuberc Lung Dis. 2008. Feb;12(2):225–7. [PubMed] [Google Scholar]
- 4.Cranmer LM, Kanyugo M, Jonnalagadda SR, Lohman-Payne B, Sorensen B, Maleche Obimbo E, et al. High prevalence of tuberculosis infection in HIV-1 exposed Kenyan infants. Pediatr Infect Dis J. 2014. Apr;33(4):401–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Maritz E, Montepiedra G, Liu L, Mitchell C, Madhi S, Bobat R, et al. Source Case Identification in HIV- exposed infants and Tuberculosis diagnosis in an Isoniazid prevention study. Int J Tuberc Lung Dis Off J Int Union Tuberc Lung Dis. 2016. Aug;20(8):1060–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Shapiro RL, Lockman S. Mortality among HIV-Exposed Infants: The First and Final Frontier. Clin Infect Dis. 2010. Feb 1;50(3):445–7. [DOI] [PubMed] [Google Scholar]
- 7.Kidzeru EB, Hesseling AC, Passmore JAS, Myer L, Gamieldien H, Tchakoute CT, et al. In-utero exposure to maternal HIV infection alters T-cell immune responses to vaccination in HIV-uninfected infants. AIDS Lond Engl. 2014. Jun 19;28(10):1421–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Jones CE, Hesseling AC, Tena-Coki NG, Scriba TJ, Chegou NN, Kidd M, et al. The impact of HIV exposure and maternal Mycobacterium tuberculosis infection on infant immune responses to bacille Calmette-Guérin vaccination. AIDS Lond Engl. 2015. Jan 14;29(2):155–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Marquez C, Chamie G, Achan J, Luetkemeyer AF, Kyohere M, Okiring J, et al. Tuberculosis Infection in Early Childhood and the Association with HIV-Exposure in HIV-Uninfected Children in Rural Uganda. Pediatr Infect Dis J. 2016. May;35(5):524–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Madhi SA, Nachman S, Violari A, Kim S, Cotton MF, Bobat R, et al. Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children. N Engl J Med. 2011. Jul 7;365(1):21–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Kenya National HIV Survey 2020. Kenya’s National HIV Survey Shows Progress Towards Control of the Epidemic. Nairobi, 20th February 2020 – MINISTRY OF HEALTH [Internet]. [cited 2022 Sep 19]. Available from: https://www.health.go.ke/kenyas-national-hiv-survey-shows-progress-towards-control-of-the-epidemic-nairobi-20th-february-2020/
- 12.Cobelens FG, Egwaga SM, Ginkel T van, Muwinge H, Matee MI, Borgdorff MW. Tuberculin Skin Testing in Patients with HIV Infection: Limited Benefit of Reduced Cutoff Values. Clin Infect Dis. 2006. Sep 1;43(5):634–9. [DOI] [PubMed] [Google Scholar]
- 13.Cobelens F, Van Deutekom H, Draayer-Jansen I, Schepp-Beelen A, Van Gerven P, Mensen M. Tuberculin skin test reactions by time of reading among Dutch travellers. Int J Tuberc Lung Dis Off J Int Union Tuberc Lung Dis. 2003. Aug;7(8):758–63. [PubMed] [Google Scholar]
- 14.Kaplan SR, Escudero JN, Mecha J, Richardson BA, Maleche-Obimbo E, Matemo D, et al. Interferon Gamma Release Assay and Tuberculin Skin Test Performance in Pregnant Women Living With and Without HIV. J Acquir Immune Defic Syndr 1999. 2022. Jan 1;89(1):98–107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Kenya Ministry of Health. Kenyan Ministry of Health. Guidelines for management of Tuberculosis and Leprosy in Kenya. July 2013. ed2013. 2013. [Google Scholar]
- 16.Johnson DF, Malone LL, Zalwango S, Mukisa Oketcho J, Chervenak KA, Thiel B, et al. Tuberculin skin test reversion following isoniazid preventive therapy reflects diversity of immune response to primary Mycobacterium tuberculosis infection. PloS One. 2014;9(5):e96613. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.LaCourse SM, Escudero JN, Mecha J, Warr AJ, Richardson BA, Carimo N, et al. Cumulative Mycobacterium tuberculosis Infection Incidence (Measured Primarily by Tuberculin Skin Test) Among Infants With Human Immunodeficiency Virus Exposure: Observational Follow-up of an Isoniazid Prophylaxis Trial. Clin Infect Dis. 2022. May 24;ciac393. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.LaCourse SM, Richardson BA, Kinuthia J, Warr AJ, Maleche-Obimbo E, Matemo D, et al. Infant TB Infection Prevention Study (iTIPS): a randomised trial protocol evaluating isoniazid to prevent M. tuberculosis infection in HIV-exposed uninfected children. BMJ Open. 2020. Jan 21;10(1):e034308. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Martinez L, le Roux DM, Barnett W, Stadler A, Nicol MP, Zar HJ. Tuberculin skin test conversion and primary progressive tuberculosis disease in the first 5 years of life: a birth cohort study from Cape Town, South Africa. Lancet Child Adolesc Health. 2018. Jan 1;2(1):46–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Koyanagi A, Humphrey JH, Ntozini R, Nathoo K, Moulton LH, Iliff P, et al. Morbidity among human immunodeficiency virus-exposed but uninfected, human immunodeficiency virus-infected, and human immunodeficiency virus-unexposed infants in Zimbabwe before availability of highly active antiretroviral therapy. Pediatr Infect Dis J. 2011. Jan;30(1):45–51. [DOI] [PubMed] [Google Scholar]
- 21.Torre PI, Zeldow B, Hoffman HJ, Buchanan A, Siberry GK, Rice M, et al. Hearing Loss in Perinatally HIV-infected and HIV-exposed but Uninfected Children and Adolescents. Pediatr Infect Dis J. 2012. Aug;31(8):835. [DOI] [PMC free article] [PubMed] [Google Scholar]
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