Newly diagnosed HIV positive children may be unique index cases to identify undiagnosed parents. Data was used from the Pediatric Urgent Start of HAART (NCT02063880) trial, which enrolled hospitalized, ART-naïve, HIV positive children ages 0–12 years in Kenya. Exact McNemar’s tests were used to compare proportions of mothers and fathers tested for HIV, linked to care, and on ART at baseline and 6 months. This analysis included 87 newly diagnosed children with HIV who completed 6 months of follow-up. Among 83 children with living mothers, there were improvements in maternal linkage to care and treatment comparing baseline to 6 months (36% vs. 78%; p < 0.0001 and 22% vs. 52%; p < 0.0001). Among 80 children with living fathers, there were increases from baseline to 6 months in the number of fathers who knew the child’s HIV status (34% vs. 78%; p < 0.0001), fathers ever tested for HIV (43% vs. 65%; p < 0.0001), fathers ever tested HIV positive (21% vs. 43%; p < 0.0001), fathers ever linked to care (15% vs. 35%; p < 0.0001), and fathers ever initiated on ART (11% vs. 23%; p = 0.0039). Newly diagnosed HIV positive children can be important index cases to identify parents with undiagnosed HIV or poor engagement in care.

Background: Completion of tuberculosis (TB) preventive treatment is important to optimize efficacy; treatment-related adverse events (AEs) sometimes result in discontinuation. This study describes the occurrence of AEs and their risk factors during a 6-month, 2-drug, fluoroquinolone-based preventive treatment for household contacts of patients with drug-resistant TB in Karachi, Pakistan. Methods: The primary outcome was development of any clinical AE during preventive treatment. Adverse events were categorized using the AE grading tables of the National Institutes of Health. Time-to-event analysis with Kaplan-Meier curves and Cox proportional hazards models accounting for recurrence were used to analyze associated risk factors. Results: Of the 172 household contacts on preventive treatment, 36 (21%) developed 64 AEs during 813 months of treatment. The incidence of AEs over 6 months of treatment was 7.9 per 100 person-months; 16 per 100 person-months with a fluoroquinolone and ethionamide, and 4.4 per 100 person-months with a fluoroquinolone and ethambutol. There were 53 (83%) grade 1 and 11 grade 2 AEs, with no grade 3 or 4 AEs. In multivariable analysis, the risk of AEs was higher in contacts prescribed ethionamide as compared to ethambutol adjusting for age, sex, and body mass index (adjusted hazard ratio, 2.1 [95% confidence interval {CI}, 1.2-3.6]). Overall, there was no notable difference in treatment completion among the contacts who experienced an AE and those who did not (crude odds ratio, 1.1 [95% CI,. 52-2.5]). Conclusions: A fluoroquinolone-based preventive treatment regimen for drug-resistant TB exposure is well tolerated. Regimens with ethionamide are more likely to result in AEs.

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.

Background: Peripartum immunologic changes may affect latent tuberculosis infection (LTBI) diagnostic performance among HIVinfected women. Methods: HIV-infected women were serially tested with tuberculin skin test (TST) and interferon gamma release assay [QuantiFERON TB Gold In-tube (QFT)] in pregnancy and 6 weeks postpartum in Kenya. Prevalence, sensitivity and agreement, and correlates of QFT/TST positivity were assessed. Quantitative QFT mitogen and Mycobacterium tuberculosis antigen (Mtb-Ag) responses were compared by peripartum stage. Incidence of test conversion at 6 weeks postpartum was evaluated in baseline TST2/QFT2 women. Results: Among 100 HIV-infected women, median age was 26 years, median CD4 was 555 cells per cubic millimeter, and 88% were on antiretrovirals. More women were QFT+ than TST+ in both pregnancy (35.4% vs. 13.5%, P = 0.001) and postpartum (29.6% vs. 14.8%, P , 0.001). Among 18 consistently QFT+ women, 8 (44%) converted from TST2 to TST+, with improved test agreement postpartum (56.9%, k = 0.20 to 82.4%, k = 0.60). Three initially QFT2/TST2 women had test conversion (TST+ and/or QFT+), suggesting new infection (incidence 13.4/100 person-years). Mean QFT mitogen (4.46 vs. 7.64 IU/mL, P , 0.001) and Mtb-Ag (1.03 vs. 1.54 IU/mL, P = 0.03) responses were lower among all women retested in pregnancy vs. postpartum, and specifically among persistently QFT+ women (Mtb-Ag: 3.46 vs. 4.48 IU/mL, P = 0.007). QFT indeterminate rate was higher in pregnancy (16%) compared with postpartum (0%) because of lower mitogen response. Conclusions: QFT identified .2-fold more women with LTBI compared with TST in pregnancy and postpartum. Lower QFT Mtb-Ag and mitogen responses in pregnancy compared with postpartum suggest that pregnancy-associated immunologic changes may influence LTBI test performance.

BACKGROUND: Tuberculosis (TB) screening in Prevention of Mother-To-Child Transmission (PMTCT) programs is important to improve TB detection, prevention and treatment. METHODS : As part of a national PMTCT program evaluation, mother-infant pairs attending 6-week and 9-month immunization visits were enrolled at 141 maternal and child health clinics throughout Kenya. Clinics were selected using population-proportion-tosize sampling with oversampling in a high human immunodeficiency virus (HIV) prevalence region. The World Health Organization (WHO) TB symptom screen was administered to HIV-infected mothers, and associations with infant cofactors were determined. R E SULT S : Among 498 HIV-infected mothers, 165 (33%) had a positive TB symptom screen. Positive maternal TB symptom screen was associated with prior TB (P 0.04). Women with a positive TB symptom screen were more likely to have an infant with HIV infection (P 0.02) and non-specific TB symptoms, including cough (P 0.003), fever (P 0.05), and difficulty breathing (P 0.01). TB exposure was reported by 11% of the women, and 15% of the TBexposed women received isoniazid preventive therapy. CONCLUS IONS : Postpartum HIV-infected mothers frequently had a positive TB symptom screen. Mothers with a positive TB symptom screen were more likely to have infants with HIV or non-specific TB symptoms. Integration of maternal TB screening and prevention into PMTCT programs may improve maternal and infant outcomes.

Background: WHO recommends isoniazid preventive therapy (IPT) for people living with HIV (PLHIV) to prevent TB, including pregnant women. Recent trial results suggest increased adverse pregnancy outcomes associated with IPT during pregnancy. Data are limited regarding programmatic IPT use in pregnant PLHIV. Methods: We assessed previous programmatic IPT during pregnancy among HIV-infected mothers on enrolment to an infant TB prevention trial in Kenya. Pregnancy IPT use was assessed by estimated conception date assuming 38 weeks gestation. Correlates of initiation and completion were analyzed by relative risk regression, using generalized linear models with log link and Poisson family adjusted for IPT initiation year. Results: Between August 15, 2016 to June 6, 2018, 300 HIV-infected women enrolled at 6 weeks postpartum. Two-hundred twenty-four (74.7%) women reported previous IPT, of whom 155/224 (69.2%) had any pregnancy IPT use. Forty-five (29.0%) initiated pre-conception extending into early pregnancy, 41 (26.5%) initiated and completed during pregnancy, and 69 (44.5%) initiated in pregnancy and extended into early postpartum. Median gestational age at IPT pregnancy initiation was 15.1 weeks (IQR 8.3–28.4). Pregnancy/early postpartum IPT initiation was associated with new pregnancy HIV diagnosis (aRR 1.9 95%CI 1.6–2.2, p<0.001). Six-month IPT completion rates were high (147/160 [91.9%]) among women with sufficient time to complete prior to trial enrolment, and similar among pre-conception or during pregnancy initiators (aRR 0.93 [95%Cl 0.83–1.04, p=0.19]). Conclusions: Programmatic IPT use was high in pregnant PLHIV, with frequent periconception and early pregnancy initiation. Programmatic surveillance could provide further insights on pregnancy IPT implementation and maternal and infant safety outcomes.

Background: Tuberculosis (TB) during pregnancy in HIV-infected women is associated with poor maternal and infant outcomes. There are limited data on TB prevalence, optimal TB screening, and performance of rapid diagnostics in pregnant HIV-infected women. Methods: We conducted a cross-sectional study among HIV-infected pregnant women seeking antenatal care in western Kenya. After a standardized questionnaire, sputum smear microscopy for acid-fast bacilli, mycobacterial liquid culture, GeneXpert MTB/RIF (Xpert), urine lipoarabinomannan, and tuberculin skin testing were performed. We determined prevalence and correlates of culture-confirmed pulmonary TB, and compared diagnostic performance of World Health Organization (WHO) symptom screening and rapid diagnostic tests to sputum culture. Results: Between July 2013 and July 2014, we enrolled 306 women. Among 288 women with a valid sputum culture result, 54% were on antiretroviral treatment, median CD4 cell count was 437 cell per cubic millimeter (IQR 342-565), and prevalence of culture-confirmed pulmonary TB was 2.4% (confidence interval: 1.0% to 4.9%). Cough >2 weeks (P 0.04) and positive tuberculin skin testing (≥5 mm, P 0.03) were associated with pulmonary TB. Women with TB were 23-fold (95% confidence interval: 4.4 to 116.6) more likely to report a household member with TB symptoms (P 0.002). WHO symptom screen (43%), acid-fast bacilli smear (0%), Xpert (43%), and lipoarabinomannan (0%) had low sensitivity but high specificity (81%, 99%, 99%, and 95%, respectively) for pulmonary TB. Conclusions: HIV-infected pregnant women had appreciable prevalence of pulmonary TB despite modest immunosuppression. Current TB screening and diagnostic tools perform poorly in pregnant HIV-infected women. Adapted TB screening tools that include household member TB symptoms may be useful in this population.

Introduction: HIV-exposed uninfected (HEU) infants in tuberculosis (TB) endemic settings are at high risk of Mycobacterium tuberculosis (Mtb) infection and TB disease, even in the absence of known Mtb exposure. Because infancy is a time of rapid progression from primary infection to active TB disease, it is important to define when and how TB preventive interventions exert their effect in order to develop effective prevention strategies in this high-risk population. Methods and analysis: We designed a non-blinded randomised controlled trial to determine efficacy of isoniazid (INH) to prevent primary Mtb infection among HEU children. Target sample size is 300 (150 infants in each arm). Children are enrolled at 6 weeks of age from maternal and child health clinics in Kenya and are randomised to receive 12 months of daily INH ∼10 mg/kg plus pyridoxine or no INH. The primary endpoint is Mtb infection, assessed by interferon-gamma release assay QuantiFERON-TB Gold Plus (QFT-Plus) or tuberculin skin test after 12 months post-enrolment. Secondary outcomes include severe adverse events, expanded Mtb infection definition using additional QFT-Plus supernatant markers and determining correlates of Mtb infection. Exploratory analyses include a combined outcome of TB infection, disease and mortality, and sensitivity analyses excluding infants with baseline TB-specific responses on flow cytometry. Ethics and dissemination: An external and independent Data and Safety Monitoring Board monitors adverse events. Results will be disseminated through peer-reviewed journals, presentations at local and international conferences to national and global policy-makers, the local community and participants.

Background:The blood monocyte-to-lymphocyte ratio (MLR) is associated with active tuberculosis (TB) in adults but has not been evaluated as a TB diagnostic biomarker in HIV-infected children in whom respiratory sampling is difficult.Setting:In a cohort of HIV-infected hospitalized Kenyan children initiating antiretroviral therapy, absolute monocyte and lymphocyte counts were determined at enrollment and 4, 12, and 24 weeks thereafter.Methods:Children were classified as confirmed, unconfirmed, or unlikely pulmonary TB. Receiver operating characteristic curves of MLR cutoff values were generated to distinguish children with confirmed TB from those with unconfirmed and unlikely TB. General estimating equations were used to estimate change in the MLR over time by TB status.Results:Of 160 children with median age 23 months, 13 (8.1%) had confirmed TB and 67 (41.9%) had unconfirmed TB. The median MLR among children with confirmed TB {0.407 [interquartile range (IQR) 0.378-0.675]} was higher than the MLR in children with unconfirmed [0.207 (IQR 0.148-0.348), P < 0.01] or unlikely [0.212 (IQR 0.138-0.391), P = 0.01] TB. The MLR above 0.378 identified children with confirmed TB with 77% sensitivity, 78% specificity, 24% positive predictive value, and 97% negative predictive value. After TB treatment, the median MLR declined in children with confirmed TB and levels were similar to children with unlikely TB after 12 weeks.Conclusions:The blood MLR distinguished HIV-infected children with confirmed TB from those with unlikely TB and declined with TB treatment. The MLR may be a useful diagnostic tool for TB in settings where respiratory-based microbiologic confirmation is inaccessible.

Objectives: Identifying factors associated with mortality among acutely ill HIV-infected children presenting with advanced HIV disease may help clinicians optimize care for those at highest risk of death. Design: Using data from a randomized controlled trial (NCT02063880), we determined baseline sociodemographic, clinical, and laboratory cofactors of mortality among HIV-infected children in Kenya. Methods: We enrolled hospitalized, HIV-infected, antiretroviral therapy-naive children (0-12 years), initiated antiretroviral therapy, and followed up them for 6 months. We used Cox proportional hazards regression to estimate hazard ratios (HRs) for death and 95% confidence intervals (CIs). Results: Of 181 enrolled children, 39 (22%) died. Common diagnoses at death were pneumonia or suspected pulmonary tuberculosis [23 (59%)] and gastroenteritis [7 (18%)]. Factors associated with mortality in univariate analysis included age <2 years [HR 3.08 (95% CI: 1.50 to 6.33)], orphaned or vulnerable child (OVC) [HR 2.05 (95% CI: 1.09 to 3.84)], weight-for-age Z score <-2 [HR 2.29 (95% CI: 1.05 to 5.00)], diagnosis of pneumonia with hypoxia [HR 5.25 (95% CI: 2.00 to 13.84)], oral thrush [HR 2.17 (95% CI: 1.15 to 4.09)], persistent diarrhea [HR 3.81 (95% CI: 1.89 to 7.69)], and higher log10 HIV-1 viral load [HR 2.16 (95% CI: 1.35 to 3.46)] (all P < 0.05). In multivariable analysis, age <2 years and OVC status remained significantly associated with mortality. Conclusions: Young age and OVC status independently predicted mortality. Hypoxic pneumonia, oral thrush, and persistent diarrhea are important clinical features that predict mortality. Strategies to enhance early diagnosis in children and improve hospital management of critically ill HIV-infected children are needed.