Predictors of TB disease in HIV-exposed children from Southern Africa.

BACKGROUND: P1041 was a randomised, placebo-controlled isoniazid prophylaxis trial in South Africa. We studied predictors for TB in HIV-exposed children participating in the P1041 trial.METHODS: We included data from entry until Week 108. Predictors considered were type of housing, overcrowding, age, sex, ethnicity, tobacco exposure, weight-for-age percentile Z-score (WAZ), CD4%, viral load (VL), antiretroviral therapy (ART) and number of household smokers.RESULTS: Of 543 HIV-positive (HIV+) and 808 HIV-exposed uninfected (HEU) infants at entry, median age was 96 days (interquartile range: 92-105). Of 1,351 caregivers, 125 (9%) had a smoking history, and 62/1,351 reported current smoking. In 594/1,351 (44%) households, there was at least one smoker. Smoking caregivers consumed 1-5 cigarettes daily. In the HIV+ cohort, significant baseline TB predictors after adjusting covariates were as follows: WAZ (adjusted hazard ratio [aHR] 0.76, P = 0.002) and log10 HIV RNA copies/ml (aHR 1.50, P = 0.009). Higher CD4% (aHR 0.88, P = 0.002) and ART (aHR 0.50, P = 0.006) were protective. In the HEU cohort, smoking exposure was associated with reduced TB-free survival on univariate analysis, but not after adjustment in the multivariate model.CONCLUSION: Low WAZ and high VL were strong predictors of TB disease or death. Rising CD4 percentage and being on ART were protective in the HIV+ cohort.

NeoCLEAN: a multimodal strategy to enhance environmental cleaning in a resource-limited neonatal unit.

BACKGROUND: Contamination of the hospital environment contributes to neonatal bacterial colonization and infection. Cleaning of hospital surfaces and equipment is seldom audited in resource-limited settings. METHODS: A quasi-experimental study was conducted to assess the impact of a multimodal cleaning intervention for surfaces and equipment in a 30-bed neonatal ward. The intervention included cleaning audits with feedback, cleaning checklists, in-room cleaning wipes and training of staff and mothers in cleaning methods. Cleaning adequacy was evaluated for 100 items (58 surfaces, 42 equipment) using quantitative bacterial surface cultures, adenosine triphosphate bioluminescence assays and fluorescent ultraviolet markers, performed at baseline (P1, October 2019), early intervention (P2, November 2019) and late intervention (P3, February 2020). RESULTS: Environmental swabs (55/300; 18.3%) yielded growth of 78 potential neonatal pathogens with Enterococci, S. marcescens, K. pneumoniae, S. aureus and A. baumannii predominating. Highest aerobic colony counts were noted from moist surfaces such as sinks, milk kitchen surfaces, humidifiers and suction tubing. The proportion of surfaces and equipment exhibiting no bacterial growth increased between phases (P1 = 49%, P2 = 66%, P3 = 69%; p = 0.007). The proportion of surfaces and equipment meeting the ATP "cleanliness" threshold (< 200 relative light units) increased over time (P1 = 40%, P2 = 54%, P3 = 65%; p = 0.002), as did the UV marker removal rate (P1 = 23%, P2 = 71%, P3 = 74%; p < 0.001). CONCLUSION: Routine environmental cleaning of this neonatal ward was sub-optimal at baseline but improved significantly following a multimodal cleaning intervention. Involving mothers and nursing staff was key to achieving improved environmental and equipment cleaning in this resource-limited neonatal unit.

Leadership and early strategic response to the SARS-CoV-2 pandemic at a COVID-19 designated hospital in South Africa.

While many countries are preparing to face the COVID-19 pandemic, the reported cases in Africa remain low. With a high burden of both communicable and non-communicable disease and a resource-constrained public healthcare system, sub-Saharan Africa is preparing for the coming crisis as best it can. We describe our early response as a designated COVID-19 provincial hospital in Cape Town, South Africa (SA).While the first cases reported were related to international travel, at the time of writing there was evidence of early community spread. The SAgovernment announced a countrywide lockdown from midnight 26 March 2020 to midnight 30 April 2020 to stem the pandemic and save lives. However, many questions remain on how the COVID-19 threat will unfold in SA, given the significant informal sector overcrowding and poverty in our communities. There is no doubt that leadership and teamwork at all levels is critical in influencing outcomes.

COVID-19 response in low- and middle-income countries: Don't overlook the role of mobile phone communication.

Estimates of health capacities in the context of the coronavirus disease 2019 (COVID-19) pandemic indicate that most low- and middle-income countries (LMICs) are not operationally ready to manage this health emergency. Motivated by worldwide successes in other infectious disease epidemics and our experience in Sub-Saharan Africa, we support mobile phone communication to improve data collection and reporting, communication between healthcare workers, public health institutions, and patients, and the implementation of disease tracking and subsequent risk-stratified isolation measures. Programmatic action is needed for centrally coordinated reporting and communication systems facilitating mobile phones in crisis management plans for addressing the COVID-19 pandemic in LMICs. We summarize examples of worldwide mobile phone technology initiatives that have enhanced patient care and public health outcomes in previous epidemics and the current COVID-19 pandemic. In addition, we provide an overview of baseline conditions, including transparency about privacy guarantees, necessary for the successful use of mobile phones in assisting in the fight against COVID-19 spread.

Horizontal HIV transmission to children of HIV-uninfected mothers: A case series and review of the global literature.

BACKGROUND: Vertical transmission is the predominant route for acquisition of HIV infection in children, either in utero, intrapartum or postnatally through breast feeding. Less frequently, children may acquire HIV by horizontal transmission. Horizontal transmission may be healthcare-associated (infusion of HIV-contaminated blood products, use of contaminated needles, syringes and medical equipment, or through ingestion of HIV in expressed breastmilk). Community-acquired HIV transmission to children may occur following surrogate breastfeeding, pre-mastication of food, and sexual abuse. METHODS: Children with suspected horizontally acquired HIV infection were identified by retrospective folder review of existing patients (2004-2014) and by prospective interview and examination of new patients (from 2009 onwards), at a hospital-based paediatric antiretroviral clinic in Cape Town, South Africa. The global literature on horizontal HIV transmission to children (1 January 1986-1 November 2019) was reviewed, to contextualize the local findings. RESULTS: Among the 32 children with horizontal HIV transmission (15 identified retrospectively and 17 prospectively), the median age at first diagnosis was 79 months (interquartile range 28.5-91.5); most children (90.6%) had advanced HIV disease at presentation. HIV transmission was considered healthcare-associated in 15 (46.9%), community-associated in ten (31.3%), possibly healthcare or community-associated in five (15.6 %); and unknown in two children (6.3%). CONCLUSION: Horizontal HIV transmission to children is an important public health issue, with prevention efforts requiring intervention at healthcare facility- and community-level. Greater effort should be made to promptly identify and comprehensively investigate each horizontally HIV-infected child to establish possible routes of transmission and inform future prevention strategies.

Neurodevelopmental and behavioural outcomes of HIV-exposed uninfected and HIV-unexposed children at 2-3 years of age in Cape Town, South Africa.

Successful vertical HIV transmission prevention programmes (VTP) have resulted in an expanding population of HIV-exposed uninfected (HEU) infants whose growth, health and neurodevelopmental outcomes could have consequences for future resource allocation. We compared neurodevelopmental and behavioural outcomes in a prospective cohort of 2-3 year old HEU and HIV-unexposed uninfected (HU) children.Women living with and without HIV and their infants were enrolled within three days of birth from a low-risk midwife obstetric unit in Cape Town, South Africa during 2012 and 2013, under WHO Option A VTP guidelines. HIV-uninfected children aged 30-42 months were assessed using the Bayley scales of Infant Development-Third edition (BSID) and Strengths and Difficulties questionnaire (SDQ).Thirty-two HEU and 27 HU children (mean birth weight 3048g vs 3096g) were assessed. HEU children performed as well as HU children on BSID cognitive, language and motor domains. Mean scores fell within the low average range. Mothers of HEU children reported fewer conduct problems but stunting was associated with increased total difficulties on the SDQ.HEU and HU children's performance on the BSID was similar. In this low-risk cohort, HIV exposure did not confer additional risk. Stunting was associated with increased behavioural problems irrespective of HIV exposure.

A framework for preventing healthcare-associated infection in neonates and children in South Africa.

Healthcare-associated infection (HAI) is a frequent and serious complication affecting 4 - 8% of hospitalised children and neonates in high-income countries. The burden of HAI in South African (SA) paediatric and neonatal wards is substantial but underappreciated, owing to a lack of HAI surveillance and reporting. Maternal and child health and infection prevention are priority areas for healthcare quality improvement in the National Core Standards programme. Despite increasing recognition in SA, infection prevention efforts targeting hospitalised children and neonates are hampered by health system, institutional and individual patient factors. To ensure safe healthcare delivery to children, a co-ordinated HAI prevention strategy should promote development of infection prevention norms and policies, education, patient safety advocacy, healthcare infrastructure, surveillance and research. We present a framework for SA to develop and expand HAI prevention in hospitalised neonates and children.

Use of antiretrovirals in HIV-infected children in a tuberculosis prevention trial: IMPAACT P1041.

SETTING: International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1041, a tuberculosis (TB) prevention trial conducted among children enrolled from 2004 to 2008 during South Africa's roll-out of combination antiretroviral therapy (ART). OBJECTIVE: To estimate TB incidence and mortality and the effect of ART. DESIGN: Children were pre-screened to exclude TB disease and exposure, actively screened 3-monthly for TB exposure and symptoms, and provided post-exposure isoniazid prophylaxis therapy (IPT). TB diagnoses were definite, probable, or possible, and mortality all-cause. Testing was at the 5% significance level. RESULTS: In 539 children (aged 3-4 months) followed up for a median of 74 weeks (interquartile range [IQR] 48-116), incidence/100 person-years (py) was 10.67 (95%CI 8.47-13.26) for any TB and 2.89 (95%CI 1.85-4.31) for definite/probable TB. Any TB incidence was respectively 9.39, 13.59, and 9.83/100 py before, <180 days after, and 180 days after ART initiation. Adjusted analysis showed a non-significant increase in any TB (HR 1.32, 95%CI 0.71-2.52, P = 0.38) and a significant reduction in mortality (HR 0.39, 95%CI 0.17-0.82, P = 0.017) following ART initiation. CONCLUSIONS: ART reduced mortality but not TB incidence in human immunodeficiency virus (HIV) infected children in IMPAACT P1041, possibly attributable to active screening for TB exposure and symptoms with post-exposure IPT. Research into this as a strategy for TB prevention in high HIV-TB burden settings may be warranted.

Burden, spectrum, and impact of healthcare-associated infection at a South African children's hospital.

BACKGROUND: In most African countries the prevalence and effects of paediatric healthcare-associated infection (HCAI) and human immunodeficiency virus (HIV) infection are unknown. AIM: To investigate the burden, spectrum, risk factors, and impact of paediatric HCAI by prospective clinical surveillance at a South African referral hospital. METHODS: Continuous prospective clinical and laboratory HCAI surveillance using Centers for Disease Control and Prevention (CDC)/National Healthcare Safety Network (NHSN) definitions was conducted at Tygerberg Children's Hospital, South Africa, from May 1st to October 31st in 2014 and 2015. Risk factors for HCAI and associated mortality were analysed with multivariate logistic regression; excess length of stay was estimated using a confounder and time-matching approach. FINDINGS: HCAI incidence density was 31.1 per 1000 patient-days (95% CI: 28.2-34.2); hospital-acquired pneumonia (185/417; 44%), urinary tract infection (UTI) (45/417; 11%), bloodstream infection (BSI) (41/417; 10%), and surgical site infection (21/417; 5%) predominated. Device-associated HCAI incidence in the paediatric intensive care unit (PICU) was high: 15.9, 12.9 and 16 per 1000 device-days for ventilator-associated pneumonia, central line-associated BSI and catheter-associated UTI, respectively. HCAI was significantly associated with PICU stay (odds ratio: 2.0), malnutrition (1.6), HIV infection (1.7), HIV exposure (1.6), McCabe score 'fatal' (2.0), comorbidities (1.6), indwelling devices (1.9), blood transfusion (2.5), and transfer in (1.4). Two-thirds of paediatric deaths were HCAI-associated, occurring at a median of four days from HCAI onset with significantly higher crude mortality for HCAI-affected vs HCAI-unaffected hospitalizations [24/325 (7.4%) vs 12/1022 (1.2%); P<0.001]. HCAI resulted in US$371,887 direct costs with an additional 2275 hospitalization days, 2365 antimicrobial days, and 3575 laboratory investigations. CONCLUSION: HCAI was frequent with significant morbidity, mortality, and healthcare costs. Establishment of HCAI surveillance and prevention programmes for African children is a public health priority.

Early Antiretroviral Therapy in HIV-Infected Children Is Associated with Diffuse White Matter Structural Abnormality and Corpus Callosum Sparing.

BACKGROUND AND PURPOSE: Fractional anisotropy in the frontal white matter, corpus callosum, and internal capsule is abnormal in human immunodeficiency virus-positive (HIV+) adults. We describe the distribution and nature of white matter abnormalities in a cohort of children who started antiretroviral therapy within the first year of life and the benefit of early treatment by using DTI measures (fractional anisotropy and mean, axial, and radial diffusion). MATERIALS AND METHODS: DTI was performed on children in a neurodevelopmental substudy from the Children with HIV Early Antiretroviral trial. Voxel-based group comparisons were obtained to determine regions where fractional anisotropy and mean diffusion differed between HIV+ and uninfected children. Associations of DTI parameters with the timing of antiretroviral therapy initiation were examined. RESULTS: Thirty-nine HIV+ children (15 boys; mean age, 5.4 years) and 13 controls (5 boys; mean age, 5.7 years) were scanned. Two clusters with lower fractional anisotropy and 7 clusters with increased mean diffusion were identified in the HIV+ group, with symmetric distribution predominantly due to increased radial diffusion, suggestive of decreased myelination. Corticospinal tracts rather than the corpus callosum were predominantly involved. Children on early-interrupted antiretroviral therapy had lower fractional anisotropy compared with those receiving continuous treatment. CONCLUSIONS: HIV+ children at 5 years of age have white matter abnormalities measured by fractional anisotropy, despite early antiretroviral therapy, suggesting that early antiretroviral therapy does not fully protect the white matter from either peripartum or in utero infection. In contrast to adults, the corticospinal tracts are predominantly involved rather than the corpus callosum, possibly due to early antiretroviral therapy. Continuous early antiretroviral therapy can limit white matter damage.

Source case identification in HIV-exposed infants and tuberculosis diagnosis in an isoniazid prevention study.

BACKGROUND: Identifying source cases of children exposed to tuberculosis (TB) is challenging. We examined the time-point of obtaining contact information of TB source cases in human immunodeficiency virus (HIV) infected and HIV-exposed uninfected (HEU) children in a randomised, placebo-controlled trial of pre-exposure to isoniazid prophylaxis. METHODS: A total of 543 HIV-infected and 808 HEU infants without TB exposure aged 3-4 months were enrolled between 2004 and 2008. At 3-monthly follow-up, infants were evaluated for TB and care givers were asked about new TB exposure. RESULTS: In total, 128 cases of TB disease and 40 deaths were recorded among 19% (105/543) of the HIV-infected and 8% (63/808) of the HEU children; 229 TB contact occasions were reported in 205/1351 (15%) children, of which 83% (189/229) were in the household. Of the 189 household contacts, 108 (53%) underwent microbiological evaluations; 81% (87/108) were positive. HIV-infected and HEU infants had similar frequencies of TB contact: in 48% of infants with definite TB, 58% with probable TB and 43% with possible TB. Of 128 children diagnosed with TB, a TB contact was identified for 59. Of these, 29/59 (49%) were identified at or after the child's TB diagnosis. CONCLUSION: TB source cases are often identified at or after a child's TB diagnosis. More effort is required for earlier detection.

Surveillance of healthcare-associated infection in hospitalised South African children: Which method performs best?

BACKGROUND: In 2012, the South African (SA) National Department of Health mandated surveillance of healthcare-associated infection (HAI), but made no recommendations of appropriate surveillance methods. METHODS: Prospective clinical HAI surveillance (the reference method) was conducted at Tygerberg Children's Hospital, Cape Town, from 1 May to 31 October 2015. Performance of three surveillance methods (point prevalence surveys (PPSs), laboratory surveillance and tracking of antimicrobial prescriptions) was compared with the reference method using surveillance evaluation guidelines. Factors associated with failure to detect HAI were identified by logistic regression analysis. RESULTS: The reference method detected 417 HAIs among 1 347 paediatric hospitalisations (HAI incidence of 31/1000 patient days; 95% confidence interval (CI) 28.2 - 34.2). Surveillance methods had variable sensitivity (S) and positive predictive value (PPV): PPS S = 24.9% (95% CI 21 - 29.3), PPV = 100%; laboratory surveillance S = 48.4% (95% CI 43.7 - 53.2), PPV = 55.2% (95% CI 50.1 - 60.2); and antimicrobial prescriptions S = 66.4% (95% CI 61.8 - 70.8%), PPV = 88.5% (95% CI 84.5 - 91.6). Combined laboratory-antimicrobial surveillance achieved superior HAI detection (S = 84.7% (95% CI 80.9 - 87.8%), PPV = 97% (95% CI 94.6 - 98.4%)). Factors associated with failure to detect HAI included patient transfer (odds ratio (OR) 2.0), single HAI event (OR 2.8), age category 1 - 5 years (OR 2.1) and hospitalisation in a general ward (OR 2.3). CONCLUSIONS: Repeated PPSs, laboratory surveillance and/or antimicrobial prescription tracking are feasible HAI surveillance methods for low-resource settings. Combined laboratory-antimicrobial surveillance achieved the best sensitivity and PPV. SA paediatric healthcare facilities should individualise HAI surveillance, selecting a method suited to available resources and practice context.

Understanding NIH clinical case definitions for pediatric intrathoracic TB by applying them to a clinical trial.

SETTING: Standardized clinical case definitions represent the best option for pediatric tuberculosis (TB) disease diagnosis and classification. OBJECTIVE: To apply published guidelines for intrathoracic TB classification for use in reporting diagnostic studies with passive case finding to presumed TB patients from International Maternal Pediatric Adolescent AIDS Clinical Trials P1041, a trial of isoniazid prophylaxis in healthy human immunodeficiency virus exposed, bacille Calmette-Guérin vaccinated infants which employed active surveillance to assess a novel application of these guidelines in this setting. METHODS: P1041 presumed TB patients were retrospectively cross-classified by protocol-defined and National Institutes of Health (NIH) classifications, and agreement was assessed. RESULTS: Of 219 TB suspects, 166 had signs/symptoms, with 158 considered TB (21 confirmed, 92 probable, 45 possible) and 8 not TB (6 TB unlikely, 2 alternative diagnoses). Weight loss and failure to thrive represented the majority of the observed signs/symptoms. Among those with signs/symptoms, agreement between definitions was poor. Furthermore, 53 TB presumptives were without signs/symptoms, including 33 classified by the P1041 protocol as TB. CONCLUSION: Poor agreement between P1041 and NIH classifications reflects cases identified through active vs. passive surveillance, the latter reflecting the intended use of NIH definitions. Given the interest in standardized definitions for broader application, future efforts could focus on expanding TB disease classification to presumed TB patients identified through active surveillance.

Isoniazid preventive therapy in HIV-infected children on antiretroviral therapy: a pilot study.

SETTING: Tuberculosis (TB) is a common cause of mortality and morbidity in children infected with the human immunodeficiency virus (HIV). Data on isoniazid preventive therapy (IPT) efficacy in HIV-infected children receiving antiretroviral therapy (ART) are inconclusive. OBJECTIVE: To assess the efficacy, tolerability and safety of isoniazid (INH) in HIV-infected children on ART. DESIGN: A pilot randomised controlled study of INH was undertaken in HIV-infected children on ART. The primary outcome measure was TB disease or death. RESULTS: A total of 167 children were randomised to receive INH (n = 85) or placebo (n = 82), and followed for a median of 34 months (interquartile range [IQR] 24-52). The median age was 35 months (IQR 15-65). There was one death in a child on INH and none in the placebo group. Eleven (6.6%) cases of TB occurred, 4 (5%) in the INH and 7 (9%) in the placebo group. Among the TB cases, 5 were culture confirmed-2 in the INH group and 3 in the placebo group, all susceptible to INH. Severe adverse events occurred rarely (n = 6; 2%). CONCLUSION: IPT is safe and well tolerated in HIV-infected children on concomitant ART. This study supports the need for a larger study to assess efficacy in HIV-infected children living in TB-endemic areas.

Pharmacokinetics of isoniazid in low-birth-weight and premature infants.

Isoniazid (INH) is recommended for use as posttuberculosis exposure preventive therapy in children. However, no pharmacokinetic data are available for INH treatment in low-birth-weight (LBW) infants, who undergo substantial developmental and physiological changes. Our objectives in this study were to determine the pharmacokinetic parameters of INH at a dose of 10 mg/kg of body weight/day and to define its pharmacokinetics relative to the arylamine N-acetyltransferase-2 (NAT2) genotype. An intensive prospective pharmacokinetic sampling study was conducted at Tygerberg Children's Hospital, South Africa, in which we measured INH blood plasma concentrations at 2, 3, 4 and 5 h postdose. Twenty LBW infants (14 male, 16 exposed to HIV) were studied. The median birth weight was 1,575 g (interquartile range, 1,190 to 2,035 g) and the median gestational age was 35 weeks (interquartile range, 34 to 38 weeks). The NAT2 acetylation statuses of the infants were homozygous slow (SS) (5 infants), heterozygous intermediate (FS) (11 infants), and homozygous fast (FF) (4 infants). Using a noncompartmental analysis approach, the median maximum drug concentration in blood serum (Cmax) was 5.63 µg/ml, the time after drug administration to reach CmaxTmax) was 2 h, the area under the concentration-time curve from 2 to 5 h (AUC2-5) was 13.56 µg · h/ml, the half-life (t1/2) was 4.69 h, and the elimination constant rate (kel) was 0.15 h(-1). The alanine aminotransferase levels were normal, apart from 2 isolated values at two and three times above the normal levels. Only the three-times-elevated value was repeated at 6 months and normalized. All LBW infants achieved target INH blood plasma concentrations comparable to the adult values. Reduced elimination was observed in smaller and younger infants and in slow acetylators, cautioning against higher doses. The safety data, although limited, were reassuring. More data, however, are required for newborn infants.

Requirements for the clinical evaluation of new anti-tuberculosis agents in children.

The ultimate goal of evidence-based drug treatment is to produce a desired pharmacological response in a predictable manner and also to minimise adverse effects. This goal requires not only an increased awareness of the need to provide specific dosing recommendations aimed at specific patient groups, but also the implementation of a consistent integrative approach to recognise all factors contributing to the within- and between-subject variability in drug disposition and response. The assessment of new anti-tuberculosis agents and regimens in children requires a specific programme of investigation, and should be included early in human drug evaluation programmes. Appreciation of this principle is an important step forward towards the full integration of children into the tuberculosis research agenda and control programmes. The development of anti-tuberculosis drug formulations and regimens tailored to the requirements of children needs to consider physiological age-related differences for pharmacokinetics and toxicity between adults and children. Research based on these principles will create an evidence base that will inform the appropriate treatment of children with novel agents and regimens and will also inform future research, including the use of chemoprophylaxis and treatment-shortening strategies in children.

The Cough Cylinder: a tool to study measures against airborne spread of (myco-) bacteria.

BACKGROUND: 'Covering your cough' reduces droplet number, but its effect on airborne pathogen transmission is less clear. The World Health Organization specifically recommends cough etiquette to prevent the spread of Mycobacterium tuberculosis, but implementation is generally poor and evidence supporting its value is lacking. METHODS: We constructed a model to assess 'real life' transmission risk by counting viable pathogens from aerosols produced by coughing patients, thus allowing the assessment of outward protection measures in a standardised fashion. During the validation process, we focused on rod-shaped bacteria as surrogates for M. tuberculosis. RESULTS: The Cough Cylinder enabled us to sample Pseudomonas aeruginosa, Escherichia coli and mycobacteria from aerosols produced by patients with cystic fibrosis, primary ciliary dyskinesia and tuberculosis. Pathogens in droplets and in airborne particles could be sampled. Delayed air sampling allowed specific measurement of persistent airborne particles. CONCLUSION: This novel experimental system allows measurement of aerosol pathogen spread in a highly standardised fashion. It also offers the possibility to assess the impact of different interventions to limit aerosol transmission.

Safety of long-term isoniazid preventive therapy in children with HIV: a comparison of two dosing schedules.

SETTING: Two paediatric hospitals in Cape Town, South Africa. OBJECTIVE: To investigate the incidence of and risk factors for severe liver injury in human immunodeficiency virus (HIV) infected children receiving long-term isoniazid preventive therapy (IPT). DESIGN: Randomised trial of IPT or placebo given daily or thrice weekly to HIV-infected children aged ≥8 weeks; placebo was discontinued early. Alanine transaminase (ALT) was measured at baseline, 6-monthly and during illness: an increase of ≥10 times the upper limit of normal defined severe liver injury. RESULTS: Of 324 children enrolled, 297 (91.6%) received IPT (559.1 person-years [py]). Baseline median age was 23 months (interquartile range [IQR] 9.5-48.6) and median CD4%, 20% (IQR 13.6-26.9). A total of 207 (63.9%) children received combination antiretroviral therapy: 19 developed severe liver injury, 16 while receiving IPT. Among these there were 8 cases of viral hepatitis (5 with hepatitis A), 2 antiretroviral-induced liver injuries and 1 case of abdominal tuberculosis. IPT-related severe liver injury occurred in 1.7% (5/297, 0.78/100 py). No child developed hepatic failure; one died of an unrelated cause. All surviving children subsequently tolerated IPT. CONCLUSIONS: This study suggests that long-term IPT has a low toxicity risk in HIV-infected children. In the absence of chronic viral hepatitis, IPT can be safely re-introduced following recovery from liver injury.

High tuberculosis exposure among neonates in a high tuberculosis and human immunodeficiency virus burden setting.

BACKGROUND: Maternal and neonatal tuberculosis (TB) are under-recognised, particularly in settings with a high burden of human immunodeficiency virus (HIV) infection. DESIGN AND SETTING: Retrospective audit of neonates routinely screened for TB in a South African hospital during 2009. Surveillance sources reviewed included routine clinical, laboratory and pharmacy records. RESULTS: Among 70 neonates (60% HIV-exposed) screened for TB, the median gestational age was 35.5 weeks (IQR 33-38), and the median birth weight was 2000 g (IQR 1530-2484). The neonates were grouped according to a history of documented TB exposure: maternal TB in 41/70 (59%), suspected maternal TB in 9/70 (13%), other documented household TB exposure in 5/70 (7%), and no known TB exposure 15/70 (21%). Of the 50 neonates exposed to confirmed or suspected maternal TB, 36 (72%) were initiated on TB chemoprophylaxis, 5 (10%) received TB treatment and 9 (18%) received no intervention. Eight (8/50, 16%) were diagnosed with TB, all of whom were born to mothers with suspected or proven TB. CONCLUSIONS: Maternal TB, primarily among HIV-infected women, was the main indication for TB screening of neonates. Routine TB screening of pregnant women and TB care in mothers and infants should be improved in settings with a high burden of TB and HIV.