HIV matters when diagnosing TB in young children: an ancillary analysis in children enrolled in the INPUT stepped wedge cluster randomized study.

BACKGROUND: Children under age five years, particularly those living with HIV (CLHIV), are at risk for rapid progression of tuberculosis (TB). We aimed to describe TB clinical presentations, diagnostic pathways and treatment outcomes in CLHIV compared to children without HIV in Cameroon and Kenya. METHODS: This sub-analysis of a cluster-randomized trial evaluating the integration of pediatric TB services from May 2019 to March 2021 enrolled children age < 5 years with TB. We estimated the HIV infection rate with 95% confidence interval (CI). We compared TB clinical presentations, diagnostic pathways and treatment outcomes in CLHIV and children without HIV. Finally, we investigated whether HIV infection was associated with a shorter time to TB diagnosis (≤ 3 months from symptoms onset) after adjusting for covariates. Univariable and multivariable logistic regression analysis were performed with adjusted odds ratios (AORs) presented as measures of the association of covariates with HIV status and with shorter time to TB diagnosis. RESULTS: We enrolled 157 children with TB (mean age was 1.5 years) and 22/157 (14.0% [9.0-20.4%]) were co-infected with HIV. CLHIV were more likely to initially present with acute malnutrition (AOR 3.16 [1.14-8.71], p = 0.027). Most TB diagnoses (140/157, 89%) were made clinically with pulmonary TB being the most common presentation; however, there was weak evidence of more frequent bacteriologic confirmation of TB in CLHIV, 18% vs. 9% (p = 0.067), due to the contribution of lateral-flow urine lipoarabinomannan to the diagnosis. HIV positivity (AOR: 6.10 [1.32-28.17], p = 0.021) was independently associated with a shorter time to TB diagnosis as well as fatigue (AOR: 6.58 [2.28-18.96], p = 0.0005), and existence of a household contact diagnosed with TB (AOR: 5.60 [1.58-19.83], p = 0.0075), whereas older age (AOR: 0.35 [0.15-0.85], p = 0.020 for age 2-5 years), night sweats (AOR: 0.24 [0.10-0.60], p = 0.0022) and acute malnutrition (AOR: 0.36 [0.14-0.92], p = 0.034) were associated with a delayed diagnosis. The case fatality rate was 9% (2/22) in CLHIV and 4% (6/135) in children without HIV, p = 0.31. CONCLUSIONS: These results altogether advocate for better integration of TB services into all pediatric entry points with a special focus on nutrition services, and illustrate the importance of non-sputum-based TB diagnostics especially in CLHIV. TRIAL REGISTRATION: NCT03862261, first registration 05/03/2019.

Pharmacokinetics, Placental and Breast Milk Transfer of Antiretroviral Drugs in Pregnant and Lactating Women Living with HIV.

BACKGROUND: Remarkable progress has been achieved in the identification of HIV infection in pregnant women and in the prevention of vertical HIV transmission through maternal antiretroviral treatment (ART) and neonatal antiretroviral drug (ARV) prophylaxis in the last two decades. Millions of women globally are receiving combination ART throughout pregnancy and breastfeeding, periods associated with significant biological and physiological changes affecting the pharmacokinetics (PK) and pharmacodynamics (PD) of ARVs. The objective of this review was to summarize currently available knowledge on the PK of ARVs during pregnancy and transport of maternal ARVs through the placenta and into the breast milk. We also summarized main safety considerations for in utero and breast milk ARVs exposures in infants. METHODS: We conducted a review of the pharmacological profiles of ARVs in pregnancy and during breastfeeding obtained from published clinical studies. Selected maternal PK studies used a relatively rich sampling approach at each ante- and postnatal sampling time point. For placental and breast milk transport of ARVs, we selected the studies that provided ratios of maternal to the cord (M:C) plasma and breast milk to maternal plasma (M:P) concentrations, respectively. RESULTS: We provide an overview of the physiological changes during pregnancy and their effect on the PK parameters of ARVs by drug class in pregnancy, which were gathered from 45 published studies. The PK changes during pregnancy affect the dosing of several protease inhibitors during pregnancy and limit the use of several ARVs, including three single tablet regimens with integrase inhibitors or protease inhibitors co-formulated with cobicistat due to suboptimal exposures. We further analysed the currently available data on the mechanism of the transport of ARVs from maternal plasma across the placenta and into the breast milk and summarized the effect of pregnancy on placental and of breastfeeding on mammal gland drug transporters, as well as physicochemical properties, C:M and M:P ratios of individual ARVs by drug class. Finally, we discussed the major safety issues of fetal and infant exposure to maternal ARVs. CONCLUSIONS: Available pharmacological data provide evidence that physiological changes during pregnancy affect maternal, and consequently, fetal ARV exposure. Limited available data suggest that the expression of drug transporters may vary throughout pregnancy and breastfeeding thereby possibly impacting the amount of ARV crossing the placenta and secreted into the breast milk. The drug transporter's role in the fetal/child exposure to maternal ARVs needs to be better understood. Our analysis underscores the need for more pharmacological studies with innovative study design, sparse PK sampling, improved study data reporting and PK modelling in pregnant and breastfeeding women living with HIV to optimize their treatment choices and maternal and child health outcomes.

Evaluating adherence to medication in children and adolescents with HIV.

OBJECTIVE: The study was aimed to evaluate the relationship between pharmacy supply, self-reported treatment adherence and HIV viral load in HIV-infected children. METHODS: A retrospective (52 weeks) cohort study was conducted through the review of the existing databases. Pharmacy supply was classified as "home delivery" when the medications were delivered home and as "in pharmacy pick-up" when they were picked up at the pharmacy. Adherence was assessed through retrospective (3 days recall) self-report. Fisher's exact model, univariate and multivariate logistic regression analyses were used. SETTINGS: The study collected data on 140 HIV-infected children (<18 years). Adherence, pharmacy supply information and HIV viral loads were obtained from clinical and research databases. PATIENTS: The data from 127 HIV-infected children (60 boys and 67 girls; mean age 9.9 years) were collected. MAIN OUTCOME MEASURES: Complete adherence (100%) was reported in only 24% of patients. With 40% of patients being rarely or never completely adherent, 64% of children achieved undetectable viral loads during the study period. RESULTS: No association between pharmacy supply and self-reported adherence was found (p = 0.605). Self-reported adherence (p = 0.0328) and age (p = 0.025) were the significant predictors of reaching undetectable viral loads. Adolescents (>13 years) were significantly less likely to reach undetectable viral loads than children under 13 years (odds ratio 0.38; 95% CI 0.16 to 0.89). CONCLUSION: In our study, pharmacy supply was not associated with self-reported adherence. Most importantly, adherence and age were significant predictors of reaching undetectable viral loads.

Age-dependent pharmacokinetics of lamivudine in HIV-infected children.

The recommended dose of lamivudine in children is higher when compared with adults: 4 mg/kg vs approximately 2 mg/kg (150 mg) and administered twice a day. Limited data are available to demonstrate that this increased dose results in adequate exposure to lamivudine in children with human immunodeficiency virus (HIV) infection. Data were selected from children who were using lamivudine for at least 2 weeks before a full pharmacokinetic (PK) study was conducted. Lamivudine PK parameters were significantly related to age. The age of 6 years appeared to be a cutoff for a change in PK parameters of lamivudine, with children <6 years of age (n=17) having a median area under the curve 43% lower and a median peak plasma concentration 47% lower (both P<0.001) than older children (n=34). In conclusion, further investigation of the relationship between decreased lamivudine exposure and treatment outcome and long-term resistance development in younger children with HIV infection is warranted.

Hypokalemia in an asthmatic child from abuse of albuterol metered dose inhaler.

A case of albuterol abuse by a pediatric patient with the development of hypokalemia with electrocardiographic changes is presented. The hypokalemic effects of beta2-agonists are discussed in regard to the production of significant cardiac symptoms. Additionally, guidance regarding the evaluation of similar patients presenting in the emergency department is provided.

[Personal monitoring for the evaluation of human exposure to nitrogen dioxide in Moscow]. / Opyt ispolzovaniia personalnogo monitoringa pri opredelenii realnoi nagruzki na cheloveka dvuokisíu azota v usloviiakh Moskvy.

A method for measuring nitrogen dioxide (ND) individual exposure was developed. Levels of ND in lodgings and outside air were measured. On the whole these levels were different: in lodging air lower than outside; but if there were gas sources in lodgings it was vice versa.

[Toxicological evaluation of gamma ray-treated fresh fish in an experiment on rats]. / Toksikologicheskaia otsenka obrabotannoi gamma-luchami svezhei ryby v éksperimente na krysakh.

The effect of fish treated with gamma-beams on the animal body on the whole and on some organs and tissues was studied in chronic experiments on 4 generations of Wistar rats of both sexes. The animals' status was evaluated according to the rats' appearance, behavior, and the time-course of changes in the body weight. In rats of the basic generation, the rate of tumor occurrence and tumor sites were also examined. Morphological and biochemical investigations were carried out over time, namely after 4, 8, 12 and 17 months. The measurements were taken of blood serum and liver proteins, blood sulfhydryl groups and hemoglobin, ascorbic acid in the liver and adrenals, as well as of the activity of AST, ALT and cholinesterase in the blood serum and in the liver. In the majority of cases, the findings obtained in experimental animals did not differ from those in controls.

[Toxicological characteristics of disodium salt of N-lauroyl-L-glutamic acid--a surface-active agent used in the food processing industry]. / Toksikologicneskaia kharakteristika dinatrievoi soli N-lauroil-L-glutaminovoi kisloty--poverkhnostno-aktivnogo veshchestva dlia pishchevoi promyshlennosti.

To synthesize the disodium salt of N-lauroyl-L-glutamic acid (LG-Na2), use was made of the chloranhydride method with some modifications. The yield of the product was 85%. LG-Na2 possesses good surface-active properties and an emulsifying effect. The critical concentration of micelloformation of LG-Na2 is 6 10(-3) mol/l. LG-Na2 is a non-toxic compound. It is not cumulated in the animals' body. The LD50 for albino rats per os exceeds 10 000 mg/kg, that for mice 6500 mg/kg. It was shown in subacute experiments in rats that LG-Na2 did not produce any substantial influence on the animals' status or on some biochemical and morphological indicators of blood and organs. The authors suggest a tentative level of a safe oral action of LG-Na2 on man (10 mg per kg bw/day). LG-Na2 is likely to be widely used in food industry.