Maternal breastfeeding and education impact infant growth and development more than in-utero HIV/antiretroviral therapy exposure in context of universal antiretroviral therapy.

BACKGROUND: Exposure to HIV and antiretroviral therapy (ART) in utero may influence infant growth and development. Most available evidence predates adoption of universal ART (Option B+ ART regimens). In a recent cohort, we compared growth and development in HIV-exposed uninfected (HEU) to HIV-unexposed (HUU) infants. DESIGN: Prospective cohort study: data from Impact of Maternal HIV on Mycobacterium Tuberculosis Infection among Peripartum Women and their Infants (MiTIPS) in Western Kenya. METHODS: Women were enrolled during pregnancy. Mother-infant pairs were followed until 24 months postpartum. 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 between HEU and HUU children. RESULTS: About 51.8% (184/355) of the infants were HEU, 3.9% low birthweight (<2.5 kg), and 8.5% preterm (<37 gestational weeks). During pregnancy, all mothers of HEU received ART; 67.9% started ART prepregnancy, and 87.3% received 3TC/FTC, TDF, and EFV. In longitudinal analyses, HEU children did not differ significantly from HUU in growth or development ( P  > 0.05 for all). In the combined HEU/HUU cohort, higher maternal education was associated with significantly better growth and development: WAZ [ ß â€Š= 0.18 (95% CI 0.01-0.34)], HAZ [ ß â€Š= 0.26 (95% CI 0.04-0.48)], and development [ ß â€Š= 0.24 (95% CI 0.02-0.46)]. Breastfeeding was associated with significantly better HAZ [ ß =0.42 (95% CI 0.19-0.66)] and development [ ß â€Š=0.31 (95% CI 0.08-0.53)]. CONCLUSION: HEU children in the setting of universal maternal ART had a similar growth trajectory and development to HUU children. Breastfeeding and maternal education improved children's weight, height, and overall development irrespective of maternal HIV status.

Maternal HIV Status and Risk of Infant Mycobacterium tuberculosis Infection as Measured by Tuberculin Skin Test.

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.

Biomarker-confirmed suboptimal adherence to isoniazid preventive therapy among children with HIV in western Kenya.

OBJECTIVES: The aim of this study was to assess the level and correlates of biomarker-confirmed adherence to isoniazid (INH) preventive therapy (IPT) among children with HIV (CLHIV). DESIGN: This prospective cohort study assessed adherence among CLHIV on IPT in public sector HIV clinics from 2019 through 2020. METHODS: Adherence was assessed by pill counts or caregiver or self-reports, and urine biomarkers (in-house dipstick and Isoscreen). Both urine biomarker tests detect INH metabolites within 48 h of ingestion. Consistent adherence was defined as having positive results on either biomarker at all visits. Correlates of biomarker-confirmed nonadherence at each visit were evaluated using generalized estimating equations. The in-house dipstick was validated using Isoscreen as the reference. RESULTS: Among 97 CLHIV on IPT with adherence assessments, median age was 10 years (IQR 7-13). All were on ART at IPT initiation (median duration 46 months [IQR 4-89]); 81% were virally suppressed (<1000 copies/ml). At all visits, 59% ( n  = 57) of CLHIV reported taking at least 80% of their doses, while 39% ( n  = 38) had biomarker-confirmed adherence. Viral nonsuppression (adjusted risk ratio [aRR] = 1.65; 95% confidence interval [95% CI] 1.09-2.49) and the sixth month of IPT use (aRR = 2.49; 95% CI 1.34-4.65) were independent correlates of biomarker-confirmed nonadherence at each visit. Sensitivity and specificity of the in-house dipstick were 98.1% ( 94.7 - 99.6%) and 94.7% ( 88.1 - 98.3%) , respectively, versus Isoscreen. CONCLUSION: Biomarker-confirmed adherence to IPT was sub-optimal and was associated with viral nonsuppression and duration of IPT. Urine dipstick testing may be useful in assessing adherence to IPT in clinical care.

Isoniazid preventive therapy during infancy does not adversely effect growth among HIV-exposed uninfected children: secondary analysis of data from a randomized controlled trial.

Background: Isoniazid preventive therapy (IPT) decreases risk of tuberculosis (TB) disease; impact on long-term infant growth is unknown. In a recent randomized trial (RCT), we assessed IPT effects on infant growth without known TB exposure. Methods: The infant TB Infection Prevention Study (iTIPS) trial was a non-blinded RCT among HIV-exposed uninfected (HEU) infants in Kenya. Inclusion criteria included age 6-10 weeks, birthweight ≥2.5 kg, and gestation ≥37 weeks. Infants in the IPT arm received 10 mg/kg isoniazid daily for 12 months, while the control trial received no intervention; post-trial observational follow-up continued through 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. Results: Among 298 infants, 150 were randomized to IPT, 47.6% were females, median birthweight was 3.4 kg (interquartile range [IQR] 3.0-3.7), and 98.3% were breastfed. During the 12-month intervention period and 12-month post-RCT follow-up, WAZ and HAZ declined significantly in all children, 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 (ß=0.04 [95% CI:-0.14, 0.22]), HAZ (ß=0.14 [95% CI:-0.06, 0.34]), and WHZ [ß=-0.07 [95% CI: -0.26, 0.11]) z-scores were similar between arms as were WAZ and HAZ growth trajectories. Infants randomized to IPT had higher monthly WHZ increase (ß to 24 months 0.02 [95% CI:0.01, 0.04]) than the no-IPT arm. Conclusion: IPT administered to HEU infants did not significantly impact growth outcomes in the first two years of life.

Impact of Human Immunodeficiency Virus and Peripartum Period on Mycobacterium tuberculosis Infection Detection.

BACKGROUND: Pregnancy and human immunodeficiency virus (HIV) may influence tuberculosis infection detection using interferon (IFN)-γ release assay (QFT-Plus; Qiagen) and tuberculin skin test (TST). METHODS: Participants in Western Kenya underwent QFT-Plus and TST in pregnancy, 6 weeks postpartum (6wkPP) and 12 months postpartum (12moPP). RESULTS: 400 participants (200 with HIV [WHIV], 200 HIV-negative) enrolled during pregnancy (median 28 weeks' gestation [interquartile range, 24-30]). QFT-Plus positivity prevalence was higher than TST in pregnancy (32.5% vs 11.6%) and through 12moPP (6wkPP, 30.9% for QFT-Plus vs 18.0% for TST; 12moPP, 29.5% vs 17.1%; all P < .001), driven primarily by QFT-Plus-positive/TST-negative discordance among HIV-negative women. Tuberculosis infection test conversion incidence was 28.4/100 person-years (PY) and higher in WHIV than HIV-negative women (35.5 vs 20.9/100 PY; hazard ratio, 1.73 [95% confidence interval, 1.04-2.88]), mostly owing to early postpartum TST conversion among WHIV. Among QFT-Plus-positive participants in pregnancy, Mycobacterium tuberculosis  (Mtb)-specific IFN-γ responses were dynamic through 12moPP and lower among WHIV than HIV-negative women with tuberculosis infection at all time points. CONCLUSIONS: QFT-Plus had higher diagnostic yield than TST in peripartum women. Peripartum QFT-Plus positivity was stable and less influenced by HIV than TST. Mtb-specific IFN-γ responses were dynamic and lower among WHIV. Tuberculosis infection test conversion incidence was high between pregnancy and early postpartum, potentially owing to postpartum immune recovery.

Drop-offs in the isoniazid preventive therapy cascade among children living with HIV in western Kenya, 2015-2019.

INTRODUCTION: Isoniazid preventive therapy (IPT) can reduce the risk of tuberculosis (TB) in children living with HIV (CLHIV), but data on the outcomes of the IPT cascade in CLHIV are limited. METHODS: We evaluated the IPT cascade among CLHIV aged <15 years and newly enrolled in HIV care in eight HIV clinics in western Kenya. Medical record data were abstracted from September 2015 through July 2019. We assessed the proportion of CLHIV completing TB symptom screening, IPT eligibility assessment, IPT initiation and completion. TB incidence rate was calculated stratified by IPT initiation and completion status. Risk factors for IPT non-initiation and non-completion were assessed using Poisson regression with generalized linear models. RESULTS: Overall, 856 CLHIV were newly enrolled in HIV care, of whom 98% ([95% CI 97-99]; n = 841) underwent screening for TB symptoms and IPT eligibility. Of these, 13 (2%; 95% CI 1-3) were ineligible due to active TB and 828 (98%; 95% CI 97-99) were eligible. Five hundred and fifty-nine (68%; 95% CI 64-71) of eligible CLHIV initiated IPT; median time to IPT initiation was 3.6 months (interquartile range [IQR] 0.5-10.2). Overall, 434 (78%; 95% CI 74-81) IPT initiators completed. Attending high-volume HIV clinics (aRR = 2.82; 95% CI 1.20-6.62) was independently associated with IPT non-initiation. IPT non-initiation had a trend of being higher among those enrolled in the period 2017-2019 versus 2015-2016 (aRR = 1.91; 0.98-3.73) and those who were HIV virally non-suppressed (aRR = 1.90; 95% CI 0.98-3.71). Being enrolled in 2017-2019 versus 2015-2016 (aRR = 1.40; 1.01-1.96) was independently associated with IPT non-completion. By 24 months after IPT screening, TB incidence was four-fold higher among eligible CLHIV who never initiated (8.1 per 1000 person years [PY]) compared to CLHIV who completed IPT (2.1 per 1000 PY; rate ratio [RR] = 3.85; 95% CI 1.08-17.15), with a similar trend among CLHIV who initiated but did not complete IPT (8.2/1000 PY; RR = 4.39; 95% CI 0.82-23.56). CONCLUSIONS: Despite high screening for eligibility, timely IPT initiation and completion were suboptimal among eligible CLHIV in this programmatic cohort. Targeted programmatic interventions are needed to address these drop-offs from the IPT cascade by ensuring timely IPT initiation after ruling out active TB and enhancing completion of the 6-month course to reduce TB in CLHIV.

A CD4+ TNF+ monofunctional memory T-cell response to BCG vaccination is associated with Mycobacterium tuberculosis infection in infants exposed to HIV.

BACKGROUND: The immunologic correlates of risk of Mycobacterium tuberculosis (Mtb) infection after BCG vaccination are unknown. The mechanism by which BCG influences the tuberculin skin test (TST) remains poorly understood. We evaluated CD4+ T-cell responses in infants exposed to HIV and uninfected (HEU) who received BCG at birth and examined their role in susceptibility to Mtb infection and influence on TST induration. METHODS: HEU infants were enrolled in a randomised clinical trial of isoniazid (INH) to prevent Mtb infection in Kenya. We measured mycobacterial antigen-specific Th1 and Th17 cytokine responses at 6-10 weeks of age prior to INH randomisation and compared responses between Mtb infected and uninfected infants. Outcomes at 14 months of age included TST, QuantiFERON-Plus (QFT-Plus), and ESAT-6/CFP-10-specific non-IFN-γ cytokines measured in QFT-Plus supernatants. FINDINGS: A monofunctional mycobacterial antigen-specific TNF+ CD4+ effector memory (CCR7-CD45RA-) T-cell response at 6-10 weeks of age was associated with Mtb infection at 14 months of age as measured by ESAT-6/CFP-10-specific IFN-γ and non-IFN-γ responses (Odds Ratio 2.26; Confidence Interval 1.27-4.15; P = 0.006). Mycobacterial antigen-specific polyfunctional effector memory Th1 responses at 6-10 weeks positively correlated with TST induration in infants without evidence of Mtb infection at 14 months, an association which was diminished by INH therapy. INTERPRETATION: Induction of monofunctional TNF+ CD4+ effector memory T-cell responses may be detrimental in TB vaccine development. This study also provides mechanistic insight into the association of BCG-induced immune responses with TST induration and further evidence that TST-based diagnoses of Mtb infection in infants are imprecise. FUNDING: Thrasher Research Fund.

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.

Cumulative 24-month Mycobacterium tuberculosis infection incidence (measured primarily by tuberculin skin test [TST]) was high among human immunodeficiency virus exposed but uninfected infants (8.7 [95% confidence interval, 6.3-11.9] per 100 person-years). Trend for decreased TST positivity among infants at trial end (12 months postenrollment) randomized to isoniazid at 6 weeks of age was not sustained through observational follow-up to 24 months of age. CLINICAL TRIALS REGISTRATION: NCT02613169.

Interferon Gamma Release Assay and Tuberculin Skin Test Performance in Pregnant Women Living With and Without HIV.

BACKGROUND: HIV and pregnancy may affect latent TB infection (LTBI) diagnostics. Tuberculin skin test (TST) and newer generation QuantiFERON-TB Gold Plus (QFT-Plus) evaluations in pregnant women living with HIV (WLHIV) and without HIV are lacking. METHODS: In this cross-sectional study, pregnant women underwent TST and QFT-Plus testing during antenatal care in Kenya. We estimated LTBI prevalence and TST and QFT-Plus performances. Diagnostic agreement was assessed with kappa statistic, participant characteristics associated with LTBI and HIV were assessed with generalized linear models, and QFT-Plus quantitative responses were assessed with Mann-Whitney U test. RESULTS: We enrolled 400 pregnant women (200 WLHIV/200 HIV-negative women) at median 28 weeks gestation (interquartile range 24-30). Among WLHIV (all on antiretroviral therapy), the median CD4 count was 464 cells/mm3 (interquartile range 325-654); 62.5% (125) had received isoniazid preventive therapy. LTBI prevalence was 35.8% and similar among WLHIV and HIV-negative women. QFT-Plus testing identified 3-fold more women with LTBI when compared with TST (32% vs. 12%, P < 0.0001). QFT-Plus positivity prevalence was similar regardless of HIV status, although TB-specific antigen responses were lower in WLHIV than in HIV-negative women with LTBI (median QFT-TB1 1.05 vs. 2.65 IU/mL, P = 0.035; QFT-TB2 1.26 vs. 2.56 IU/mL, P = 0.027). TST positivity was more frequent among WLHIV than among HIV-negative women (18.5% vs 4.6%; P < 0.0001). CONCLUSIONS: QFT-Plus assay had higher diagnostic yield than TST for LTBI in WLHIV and HIV-negative women despite lower TB-specific antigen responses in WLHIV. Higher TST positivity was observed in WLHIV. LTBI diagnostic performance in the context of pregnancy and HIV has implications for clinical use and prevention studies, which rely on these diagnostics for TB infection entry criteria or outcomes.

Pulmonary tuberculosis screening in anti-retroviral treated adults living with HIV in Kenya.

BACKGROUND: People living with HIV (PLHIV) who reside in high tuberculosis burden settings remain at risk for tuberculosis disease despite treatment with anti-retroviral therapy and isoniazid preventive therapy (IPT). The performance of the World Health Organization (WHO) symptom screen for tuberculosis in PLHIV receiving anti-retroviral therapy is sub-optimal and alternative screening strategies are needed. METHODS: We enrolled HIV-positive adults into a prospective study in western Kenya. Individuals who were IPT-naïve or had completed IPT > 6 months prior to enrollment were eligible. We evaluated tuberculosis prevalence overall and by IPT status. We assessed the accuracy of the WHO symptom screen, GeneXpert MTB/RIF (Xpert), and candidate biomarkers including C-reactive protein (CRP), hemoglobin, erythrocyte sedimentation rate (ESR), and monocyte-to-lymphocyte ratio for identifying pulmonary tuberculosis. Some participants were evaluated at 6 months post-enrollment for tuberculosis. RESULTS: The study included 383 PLHIV, of whom > 99% were on antiretrovirals and 88% had received IPT, completed a median of 1.1 years (IQR 0.8-1.55) prior to enrollment. The prevalence of pulmonary tuberculosis at enrollment was 1.3% (n = 5, 95% CI 0.4-3.0%): 4.3% (0.5-14.5%) among IPT-naïve and 0.9% (0.2-2.6%) among IPT-treated participants. The sensitivity of the WHO symptom screen was 0% (0-52%) and specificity 87% (83-90%). Xpert and candidate biomarkers had poor to moderate sensitivity; the most accurate biomarker was CRP ≥ 3.3 mg/L (sensitivity 80% (28-100) and specificity 72% (67-77)). Six months after enrollment, the incidence rate of pulmonary tuberculosis following IPT completion was 0.84 per 100 person-years (95% CI, 0.31-2.23). CONCLUSIONS: In Kenyan PLHIV treated with IPT, tuberculosis prevalence was low at a median of 1.4 years after IPT completion. WHO symptoms screening, Xpert, and candidate biomarkers were insensitive for identifying pulmonary tuberculosis in antiretroviral-treated PLHIV.

A Randomized Controlled Trial of Isoniazid to Prevent Mycobacterium tuberculosis Infection in Kenyan Human Immunodeficiency Virus-Exposed Uninfected Infants.

BACKGROUND: Human immunodeficiency virus (HIV)-exposed uninfected (HEU) infants in endemic settings are at high risk of tuberculosis (TB). For infants, progression from primary Mycobacterium tuberculosis (Mtb) infection to TB disease can be rapid. We assessed whether isoniazid (INH) prevents primary Mtb infection. METHODS: We conducted a randomized nonblinded controlled trial enrolling HEU infants 6 weeks of age without known TB exposure in Kenya. Participants were randomized (1:1) to 12 months of daily INH (10 mg/kg) vs no INH. Primary endpoint was Mtb infection at end of 12 months, assessed by interferon-γ release assay (QuantiFERON-TB Gold Plus) and/or tuberculin skin test (TST, added 6 months after first participant exit). RESULTS: Between 15 August 2016 and 6 June 2018, 416 infants were screened, with 300 (72%) randomized to INH or no INH (150 per arm); 2 were excluded due to HIV infection. Among 298 randomized HEU infants, 12-month retention was 96.3% (287/298), and 88.9% (265/298) had primary outcome data. Mtb infection prevalence at 12-month follow-up was 10.6% (28/265); 7.6% (10/132) in the INH arm and 13.5% (18/133) in the no INH arm (7.0 vs 13.4 per 100 person-years; hazard ratio, 0.53 [95% confidence interval {CI}, .24-1.14]; P = .11]), and driven primarily by TST positivity (8.6% [8/93] in INH and 18.1% [17/94] in no INH; relative risk, 0.48 [95% CI, .22-1.05]; P = .07). Frequency of severe adverse events was similar between arms (INH, 14.0% [21/150] vs no INH, 10.7% [16/150]; P = .38), with no INH-related adverse events. CONCLUSIONS: Further studies evaluating TB preventive therapy to prevent or delay primary Mtb infection in HEU and other high-risk infants are warranted. CLINICAL TRIALS REGISTRATION: NCT02613169.

Urine Biomarker Assessment of Infant Adherence to Isoniazid Prophylaxis.

We assessed adherence in an infant tuberculosis prevention trial in Kenya with a urine isoniazid metabolite-detecting dipstick. Ninety-seven infants had 155 assays performed; 77 (49.7%) were found to be positive despite caregiver-reported adherence. Positive assays were associated with maternal secondary education, HIV suppression and no reported missed doses in past 3 days, suggesting caregiver education and self-medication use influenced infant adherence.