Tuberculosis in HIV-infected South African children with complicated severe acute malnutrition.

Academic tertiary referral hospital in Durban, South Africa. To describe the incidence and diagnostic challenges of tuberculosis (TB) in human immunodeficiency virus (HIV) infected children with severe acute malnutrition (SAM). Post-hoc analysis of a randomised controlled trial that enrolled antiretroviral therapy naïve, HIV-infected children with SAM. Trial records and hospital laboratory results were explored for clinical diagnoses and bacteriologically confirmed cases of TB. Negative binomial regression was used to explore associations with confirmed cases of TB, excluding cases where the clinical diagnosis was not supported by microbiological confirmation. Of 82 children enrolled in the study, 21 (25.6%) were diagnosed with TB, with bacteriological confirmation in 8 cases. Sputum sampling (as opposed to gastric washings) was associated with an increased risk of subsequent diagnosis of TB (adjusted relative risk [aRR] 1.134, 95%CI 1.02-1.26). Culture-proven bacterial infection during admission was associated with a reduced risk of TB (aRR 0.856, 95%CI 0.748-0.979), which may reflect false-negative microbiological tests secondary to empiric broad-spectrum antibiotics. TB is common in HIV-infected children with SAM. While microbiological confirmation of the diagnosis is feasible, empiric treatment remains common, possibly influenced by suboptimal testing and false-negative TB diagnostics. Rigorous microbiological TB investigation should be integrated into the programmatic management of HIV and SAM

Adolescent antiretroviral management: Understanding the complexity of non-adherence

This case-based discussion highlights challenges in adolescent antiretroviral management, focusing on non-disclosure of status and the subsequent impact of suboptimal treatment adherence. Despite the scale-up of antiretroviral therapy (ART) and recommendations made by the World Health Organization (WHO) for ART for all human immunodeficiency virus (HIV)-infected paediatric patients, ART coverage in adolescents lags behind that in adults. Challenges of sustaining lifelong ART in children and adolescents require consideration of specific behavioural, physiological and psychosocial complexities associated with this special group. To preserve future drug options and sustain lifelong access to therapy, addressing non-adherence to treatment is critical to minimising acquisition of ART drug resistance and treatment failure. We review the psychosocial and developmental components that influence the course of the disease in adolescents and consider the complexities arising from perinatal exposure to ART and the growing risk of transmitted ART drug resistance in high-burden resourcelimited settings

Distinct genital tract HIV-specific antibody profiles associated with tenofovir gel

The impact of topical antiretrovirals for pre-exposure prophylaxis on humoral responses following HIV infection is unknown. Using a binding antibody multiplex assay, we investigated HIV-specific IgG and IgA responses to envelope glycoproteins, p24 Gag and p66, in the genital tract (GT) and plasma following HIV acquisition in women assigned to tenofovir gel (n=24) and placebo gel (n=24) in the CAPRISA 004 microbicide trial to assess if this topical antiretroviral had an impact on mucosal and systemic antibody responses. Linear mixed effect modeling and partial least squares discriminant analysis was used to identify multivariate antibody signatures associated with tenofovir use. There were significantly higher response rates to gp120 Env (P=0.03), p24 (P=0.002), and p66 (P=0.009) in plasma and GT in women assigned to tenofovir than placebo gel at multiple time points post infection. Notably, p66 IgA titers in the GT and plasma were significantly higher in the tenofovir compared with the placebo arm (P<0.05). Plasma titers for 9 of the 10 HIV-IgG specificities predicted GT levels. Taken together, these data suggest that humoral immune responses are increased in blood and GT of individuals who acquire HIV infection in the presence of tenofovir gel.United States. National Institutes of Health (AI51794)United States. National Institutes of Health (AI104387)United States. National Institutes of Health (AI115981)United States. National Institutes of Health (AI116086)United States. Agency for International Development (GP00-08-00005-00 subproject agreement PPA-09-046

HIV-Associated Tuberculosis in the Newborn and Young Infant

Each year, approximately 250 000 women die during pregnancy, delivery, or postpartum. Maternal mortality rates due to tuberculosis (TB) and HIV in Sub-Saharan Africa now supersede obstetric-related causes of mortality. The majority of cases occur in population-dense regions of Africa and Asia where TB is endemic. The vertical transmission rate of tuberculosis is 15%, the overall vertical transmission rate of HIV in resource-limited settings with mono- or dual-ARV therapy varies from 1.9% to 10.7%. If the millennium development goals are to be achieved, both HIV and TB must be prevented. The essential aspect of TB prevention and detection in the newborn is the maternal history and a positive HIV status in the mother. Perinatal outcomes are guarded even with treatment of both diseases. Exclusive breast feeding is recommended. The community and social impact are crippling. The social issues aggravate the prognosis of these two diseases

Adolescents and young people at the centre: global perspectives and approaches to transform HIV testing, treatment and care

In this special issue of the Journal of the International AIDS Society, we focus on research and perspectives that put adolescents and young people at the centre of their HIV prevention and care. Globally over two million adolescents are living with HIV, while many more are at risk of HIV infection. In contrast to reductions globally and in highest burden regions in the general population, estimates suggest that HIV incidence and mortality persist among adolescents and young people. Young people continue be less likely to test for HIV, to link to care in a timely way and to stay engaged in care if they test HIV positive compared to adults. Although, these disparities in access to HIV prevention and care have been documented over the last decade, the evidence base of models, programmes and tools to address the challenges young people face is limited. This special issue documents a series of promising and effective approaches that support adolescents and young people, not only to access and use HIV prevention and care, but also to live whole and fulfilling lives. The articles in this issue bring together evidence and lessons learned from a number of global settings, unified by one clear message: young people need and want to be at the centre of their HIV prevention and care programmes

Comparison of outcomes between children ventilated in a non‐paediatric intensive care and a paediatric intensive care unit: A retrospective analysis

Background. Lack of paediatric intensive care infrastructure, human resources and expertise in low- and middle-income countries (LMICs) often results in critically ill children being managed in non-intensive-care unit (ICU) settings. Objectives. To compare the mortality between critically ill patients who required ventilation for more than 24 hours in a non-paediatric ICU (PICU) setting v. those admitted directly to a PICU. Methods. Participants were enrolled if they were between one month and 13 years of age and were ventilated in a non-PICU ward in a regional hospital and a PICU ward in a tertiary/quaternary hospital during the study period of January 2015 - December 2017 in KwaZulu- Natal, South Africa. Descriptive statistics, chi-square test, Wilcoxon test and binary logistic regression were used for data analysis. Ethics approval was obtained (approval number BE568/18 BREC) from the Biostatistics Research Council of the University of KwaZulu-Natal. Results. Of the 904 admissions, 25.1% (n=227) were admitted to non-PICU and 74.9% (n=677) to a PICU. A significantly higher proportion of non-PICU patients were malnourished than PICU patients (26.4% v. 13.3%, p<0.001). Patients ventilated in a PICU were 76% less likely to die (p<0.001), while patients who required inotropes were 15.08 (9.68 - 24.34) times more likely to die (p<0.001). There was a statistically significant association between admission setting and survival outcome, with higher mortality in the non-PICU setting than in the PICU setting (46.3% v. 19.5%, p<0.001). Conclusion. Critically ill children ventilated in a non-PICU setting in KwaZulu-Natal are more likely to be malnourished, require inotropes and have higher mortality. Although increasing access to PICU bed availability is a long-term goal, the high mortality in the non-PICU setting highlights the need to optimise the availability of resources in these non-PICU wards, optimise and train the staff, and improve primary healthcare services

Interventions addressing the adolescent HIV continuum of care in South Africa: a systematic review and modified Delphi analysis

INTRODUCTION: Compared with adults, adolescents in South Africa have larger gaps at each step of the HIV continuum of care resulting in low levels of viral suppression. METHODS: We conducted a systematic review and modified Delphi analysis of interventions addressing the HIV continuum of care for adolescents in South Africa. We searched PubMed, Science Direct, and Google Scholar and online conference proceedings from the International AIDS Society, the International AIDS Conference, and the Conference on Retrovirology and Opportunistic Infections from 1 January 2010 to 30 September 2020. We then conducted a modified Delphi analysis with 29 researchers involved in the National Institutes of Health's Fogarty International-supported Adolescent HIV Implementation Science Alliance-South Africa to evaluate interventions for efficacy, feasibility and potential for scale-up. RESULTS: We identified nine initial published articles containing interventions addressing the adolescent HIV continuum of care in South Africa, including five interventions focused on HIV diagnosis, two on antiretroviral therapy adherence and two on retention in care. No studies addressed linkage to care or transition from paediatric to adult care. Two studies discussed intervention costs. In-home and HIV self-testing, community-based adherence support, and provision of adolescent-friendly services were the most impactful and scalable interventions addressing the adolescent HIV continuum of care. CONCLUSION: Future interventions should work comprehensively across the adolescent HIV continuum of care and be tailored to the specific needs of adolescents

Abacavir pharmacokinetics in African children living with HIV: A pooled analysis describing the effects of age, malnutrition and common concomitant medications

AIMS: Abacavir is part of WHO-recommended regimens to treat HIV in children under 15 years of age. In a pooled analysis across four studies, we describe abacavir population pharmacokinetics to investigate the influence of age, concomitant medications, malnutrition and formulation. METHODS: A total of 230 HIV-infected African children were included, with median (range) age of 2.1 (0.1-12.8) years and weight of 9.8 (2.5-30.0) kg. The population pharmacokinetics of abacavir was described using nonlinear mixed-effects modelling. RESULTS: Abacavir pharmacokinetics was best described by a two-compartment model with first-order elimination, and absorption described by transit compartments. Clearance was predicted around 54% of its mature value at birth and 90% at 10 months. The estimated typical clearance at steady state was 10.7 L/h in a child weighing 9.8 kg co-treated with lopinavir/ritonavir, and was 12% higher in children receiving efavirenz. During co-administration of rifampicin-based antituberculosis treatment and super-boosted lopinavir in a 1:1 ratio with ritonavir, abacavir exposure decreased by 29.4%. Malnourished children living with HIV had higher abacavir exposure initially, but this effect waned with nutritional rehabilitation. An additional 18.4% reduction in clearance after the first abacavir dose was described, suggesting induction of clearance with time on lopinavir/ritonavir-based therapy. Finally, absorption of the fixed dose combination tablet was 24% slower than the abacavir liquid formulation. CONCLUSION: In this pooled analysis we found that children on lopinavir/ritonavir or efavirenz had similar abacavir exposures, while concomitant TB treatment and super-boosted lopinavir gave significantly reduced abacavir concentrations

Policy brief: Optimising antimicrobial usage in paediatric inpatient hospital settings

Antimicrobial resistance (AMR) poses a global threat, partly fueled by antimicrobial overuse. Paediatric inpatients are particularly vulnerable to infections, leading to high antimicrobial consumption. In low-to-middle income countries (LMICs) like South Africa, research on antimicrobial usage for neonatal and paediatric healthcare-associated infections (HAI) is limited. This cross-sectional study evaluated antimicrobial usage in three academic public sector hospitals in South Africa to improve appropriateness. 22.9% of hospitalised children received at least one prescribed antimicrobial, with neonates, infants, and adolescents having higher prescription rates for HAIs. Common antimicrobials prescribed included beta-lactamase sensitive penicillin, aminoglycosides, and carbapenems. Antimicrobial selection aligned with the WHO AWaRe classification system. HIV infection did not emerge as a risk factor for HAIs or excessive antimicrobial usage. The policy brief recommends several strategies, summarized by the acronym \u27PRACTICE,\u27 to optimize antimicrobial prescribing practices. These include implementing standardized policies for empiric antimicrobial use, routine review of antimicrobial therapy, age-specific antimicrobial stewardship programs, and continued collaborative efforts and research. Individualized treatment plans, improved infection prevention and control measures, ongoing surveillance, and exploring electronic technology for antimicrobial stewardship are also crucial. Addressing antimicrobial usage is imperative to combat the growing threat of AMR and improve patient outcomes in LMICs like South Africa

Next-generation point-of-care testing in pediatric human immunodeficiency virus infection facilitates diagnosis and monitoring of treatment

Point-of-care (PoC) testing facilitates early infant diagnosis (EID) and treatment initiation, which improves outcome. We present a field evaluation of a new PoC test (Cepheid Xpert® HIV-1 Qual XC RUO) to determine whether this test improves EID and assists the management of children living with human immunodeficiency virus (HIV) infection. We compared 2 PoC tests with the standard-of-care (SoC) test used to detect HIV infection from dry blood spots in newborn infants at high risk of in utero infection. We also evaluated the ability of the PoC tests to detect HIV total nucleic acid (TNA) in children living with HIV infection who had maintained undetectable plasma viremia following very early combination antiretroviral therapy (cART) initiation. Qualitative (Qual) detection of HIV using the Xpert® HIV-1 Qual XC RUO (“RUO”) and Xpert® HIV-1 Qual (“Qual”) PoC tests was compared in 224 infants with the SoC DBS Roche COBAS® HIV-1/HIV-2 qualitative test. The same 2 PoC tests were also evaluated in 35 older children who had initiated cART before 21 days of age and maintained undetectable plasma viremia for a mean of 25 months. No discrepancies were observed in detection of HIV infection via the 2 PoC tests or the SoC test in the 224 neonates studied, but only 95% of the SoC test results were generated compared with 100% of the PoC test results (P = .0009). The cycle threshold values for the research use only (RUO) assay were the lowest of the 3 assays (P < .0001 in each case). In 6 of the 35 early-treated aviremic children, HIV TNA was detected by RUO but not Qual. The RUO assay outperforms Qual in detecting HIV-1 infection. RUO would therefore potentially improve EID and assist in identifying cART-adherent early-treated children with the lowest HIV TNA levels and the highest HIV cure potential