Endothelial activation is associated with intestinal epithelial injury, systemic inflammation and treatment regimen in children living with vertically acquired HIV-1 infection.

BACKGROUND: Premature development of cardiovascular disease in children living with HIV-1 (CLWH) may be associated with compromised gut barrier function, microbial translocation, immune activation, systemic inflammation and endothelial activation. Biomarkers of these pathways may provide insights into pathogenesis of atherosclerotic disease in CLWH. METHODS: This was a cross-sectional study of CLWH enrolled in the multicentre Early Pediatric Initiation-Canadian Child Cure Cohort (EPIC4 ) who were on antiretroviral therapy (ART) with undetectable viral load. Plasma biomarkers of intestinal epithelial injury [intestinal fatty acid binding protein-1 (IFABP)], systemic inflammation [tumour necrosis factor (TNF) and interleukin-6 (IL-6)] and endothelial activation [angiopoietin-2 (Ang2), soluble vascular endothelial growth factor-1 (sVEGFR1) and soluble endoglin (sEng)] were quantified by enzyme-linked immunosorbent assay. Correlation and factor analysis of biomarkers were used to examine associations between innate immune pathways. RESULTS: Among 90 CLWH, 16% of Ang2, 15% of sVEGFR1 and 23% of sEng levels were elevated relative to healthy historic controls. Pairwise rank correlations between the three markers of endothelial activation were statistically significant (ρ = 0.69, ρ = 0.61 and ρ = 0.65, P < 0.001 for all correlations). An endothelial activation index, derived by factor analysis of the three endothelial biomarkers, was correlated with TNF (ρ = 0.47, P < 0.001), IL-6 (ρ = 0.60, P < 0.001) and intestinal fatty acid binding protein-1 (ρ = 0.67, P < 0.001). Current or past treatment with ritonavir-boosted lopinavir (LPV/r) was associated with endothelial activation (odds ratio = 5.0, 95% CI: 1.7-17, P = 0.0020). CONCLUSIONS: Endothelial activation is prevalent in CLWH despite viral suppression with combination ART and is associated with intestinal epithelial injury, systemic inflammation and treatment with LPV/r.

Congenital anomalies following antenatal exposure to dolutegravir: a Canadian surveillance study.

OBJECTIVE: Dolutegravir is recommended worldwide as a first-line antiretroviral therapy (ART) for individuals living with HIV. A recent study reported increased rates of neural tube defects in infants of dolutegravir-treated women. This study examined rates of congenital anomalies in infants born to women living with HIV (WLWH) in Canada. DESIGN: The Canadian Perinatal HIV Surveillance Programme captures surveillance data on pregnant WLWH and their babies and was analysed to examine the incidence of congenital anomalies. SETTING: Paediatric HIV clinics. POPULATION: Live-born infants born in Canada to WLWH between 2007 and 2017. METHODS: Data on mother-infant pairs, including maternal ART use at conception and during pregnancy, are collected by participating sites. MAIN OUTCOME MEASURES: Congenital anomalies. RESULTS: Of the 2423 WLWH, 85 (3.5%, 95% CI 2.85-4.36%) had non-chromosomal congenital anomalies. There was no evidence of a significant difference in rates of congenital anomalies between women who were on ART in their first trimester (3.9%, CI 1.7-7.6%) or later in the pregnancy (3.9%, 95% CI 2.6-5.6%). Four of the 80 (5.0%, 95% CI 1.4-12.3%) neonates born to WLWH on dolutegravir during the first trimester had congenital anomalies, none were neural tube defects (95% CI 0.00-3.10%). CONCLUSION: Despite recent evidence raising a safety concern, this analysis found no signal for increased congenital anomalies. TWEETABLE ABSTRACT: Five percent of the infants of Canadian women living with HIV on dolutegravir at conception had congenital anomalies; none had neural tube defects.

The Women and Children's Infectious Diseases Center: An integrated approach to congenital infectious diseases.

Congenital infectious diseases, transmitted during the course of pregnancy, are estimated to affect nearly one in every hundred births worldwide. These infections may be associated with fetal and infant adverse health outcomes, due to congenital malformations caused by in utero transmission of the infectious organism itself (as is the case with cytomegalovirus, toxoplasmosis, syphilis and Zika virus), or due to chronic infection in the infant (as is the case with human immunodeficiency virus [HIV] and hepatitis B and C). In addition, children who are exposed, yet uninfected, may still suffer from the consequences of exposure to infectious pathogens or to the drugs given to treat pregnant women and prevent in utero transmission (as may be the case with HIV infection).

A case series of third-trimester raltegravir initiation: Impact on maternal HIV-1 viral load and obstetrical outcomes.

OBJECTIVE: To describe the impact of initiating raltegravir (RAL)-containing combination antiretroviral therapy (cART) regimens on HIV viral load (VL) in pregnant women who have high or suboptimal VL suppression late in pregnancy. METHODS: HIV-infected pregnant women who started RAL-containing cART after 28 weeks' gestation from 2007 to 2013 were identified in two university hospital centres. RESULTS AND DISCUSSION: Eleven HIV-infected women started RAL at a median gestational age of 35.7 weeks (range 31.1 to 38.0 weeks). Indications for RAL initiation were late presentation in pregnancy (n=4) and suboptimal VL suppression secondary to poor adherence or viral resistance (n=7). Mean VL at the time of RAL initiation was 73,959 copies/mL (range <40 to 523,975 copies/mL). Patients received RAL for a median of 20 days (range one to 71 days). The mean decline in VL from the time of RAL initiation to delivery was 1.93 log, excluding one patient who received only one RAL dose and one patient with undetectable VL at the time of RAL initiation. After eight days on RAL, 50% of the women achieved a VL <1000 copies/mL (the threshold for recommended Caesarean section to reduce the risk for perinatal transmission). There were no cases of perinatal HIV transmission. CONCLUSION: The present study provides preliminary data to support the use of RAL-containing cART to expedite HIV-1 VL reduction in women who have a high VL or suboptimal VL suppression late in pregnancy, and to decrease the risk of HIV perinatal transmission while avoiding Caesarean section. Further assessment of RAL safety during pregnancy is warranted.

OBJECTIF: Décrire les répercussions de l'amorce d'une antirétrovirothérapie prophylactique associative (ARPA) contenant du raltégravir (RAL) sur la charge virale (CV) du VIH chez les femmes enceintes dont la suppression de la CV est élevée ou sous-optimale en fin de grossesse. MÉTHODOLOGIE: Les chercheurs ont extrait le dossier des femmes enceintes infectées par le VIH qui avaient amorcé une ARAP contenant du RAL après 28 semaines de grossesse dans deux centres hospitaliers universitaires entre 2007 et 2013. RÉSULTATS ET EXPOSÉ: Onze femmes infectées ont entrepris un traitement de RAL à une médiane de 35,7 semaines de grossesse (plage de 31,1 à 38,0 semaines). Les indications pour entreprendre le RAL étaient une présentation tardive au suivi de grossesse (n=4) et une suppression sous-optimale de la CV en raison d'un mauvais respect du traitement ou d'une résistance virale (n=7). La CV moyenne au début du traitement au RAL était de 73 959 copies/mL (plage de moins de 40 copies/mL à 523 975 copies/mL). Les patientes ont pris du RAL pendant une médiane de 20 jours (plage de un à 71 jours). La diminution moyenne de la CV entre le début du RAL et l'accouchement était de 1,93 log, à l'exception d'une patiente qui n'a reçu qu'une dose de RAL et d'une patiente dont la CV n'était pas décelable au moment d'entreprendre le RAL. Au bout de huit jours de RAL, 50 % des femmes présentaient une CV inférieure à 1 000 copies/mL (le seuil pour recommander une césarienne afin de réduire le risque de transmission périnatale). Il n'y a d'ailleurs eu aucun cas de transmission périnatale du VIH. CONCLUSION: La présente étude fournit des données provisoires pour soutenir l'utilisation d'ARPA contenant du RAL afin d'accélérer la réduction de la CV du VIH-1 chez les femmes qui présentaient une CV élevée ou une suppression sous-optimale de leur CV pendant la grossesse, ainsi que pour réduire le risque de transmission périnatale du VIH tout en évitant une césarienne. Une évaluation plus approfondie de l'innocuité du RAL est justifiée pendant la grossesse.

Tuberculosis in children: New diagnostic blood tests.

The interferon-gamma-release assays were developed to overcome the pitfalls and logistic difficulties of the tuberculin skin test (TST) for the diagnosis of latent tuberculosis infection (LTBI). These blood tests measure the in vitro production of interferon-gamma by sensitized lymphocytes in response to Mycobacterium tuberculosis-specific antigens. Two interferon-gamma-release assays are registered for use in Canada: the QuantiFERON-TB Gold In-Tube assay (Cellestis Inc, Australia) and the T.SPOT-TB test (Oxford Immunotec, United Kingdom). Evaluation of these tests has been hampered by the lack of a gold standard for LTBI, and limited paediatric data on their use. It appears that they are more specific than the TST, and may be useful for evaluating TST-positive patients at low risk of true LTBI. Moreover, they may add sensitivity if used in addition to the TST in immunocompromised patients, very young children and close contacts of infectious adults. A summary of these tests, their limitations and their application to clinical paediatric practice are described.

Tuberculosis in children: New diagnostic blood tests.

The interferon-gamma-release assays were developed to overcome the pitfalls and logistic difficulties of the tuberculin skin test (TST) for the diagnosis of latent tuberculosis infection (LTBI). These blood tests measure the in vitro production of interferon-gamma by sensitized lymphocytes in response to Mycobacterium tuberculosis-specific antigens. Two interferon-gamma-release assays are registered for use in Canada: the QuantiFERON-TB Gold In-Tube assay (Cellestis Inc, Australia) and the T.SPOT-TB test (Oxford Immunotec, United Kingdom). Evaluation of these tests has been hampered by the lack of a gold standard for LTBI, and limited paediatric data on their use. It appears that they are more specific than the TST, and may be useful for evaluating TST-positive patients at low risk of true LTBI. Moreover, they may add sensitivity if used in addition to the TST in immunocompromised patients, very young children and close contacts of infectious adults. A summary of these tests, their limitations and their application to clinical paediatric practice are described.