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Introduction: Children who are HIV-exposed but uninfected (CHEU) are at risk of linear growth faltering and neurodevelopmental delay. Circulating biomarkers associated with these adverse outcomes may elucidate pathways of injury. Objective: To identify biomarkers associated with growth faltering and neurodevelopmental delay in CHEU. Methods: We performed a systematic review of electronic databases MEDLINE (1946-April 2021), EMBASE (1974-April 2021), Scopus (2004-April 2021), and PubMed (1985-April 2021), following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The systematic review was registered on the International Prospective Register of Systematic Reviews (PROSPERO, registration number CRD42021238363). Results: We found seven studies associating biomarker abnormalities and growth outcomes in CHEUs and two studies on biomarker abnormalities and neurodevelopmental delay. Biomarker abnormalities associated with growth restriction were: C-reactive protein (CRP), tumour necrosis factor (TNF), interferon-gamma (IFN-γ), interleukin (IL)-12p70, IFN-γ-induced protein-10 (CXCL10/IP-10), lipopolysaccharide binding protein (LBP), insulin-like growth factor-1 (IGF-1), and IGF-binding protein-1 (IGFBP-1). Biomarkers associated with motor, language, and cognitive delay were CRP, IFN-γ, IL-1β, -2, -4, -6, -10, -12p70, neutrophil gelatinase-associated lipocalin (NGAL), granulocyte-macrophage colony-stimulating factor (GM-CSF), and matrix metalloproteinase-9 (MMP-9). Conclusion: Elevated markers of inflammation (acute phase reactants, pro-inflammatory cytokines, chemokines) and intestinal microbial translocation are associated with growth faltering. Elevated markers of inflammation are associated with adverse neurodevelopment.

Youth (aged 15 to 29 years) account for one quarter of new HIV cases in Canada. Of those, men-who-have-sex-with-men make up one third to one half of new cases in that age range. Moreover, Indigenous youth are over-represented in the proportion of new cases. The use of emtricitabine/tenofovir disoproxil fumarate as pre-exposure prophylaxis (PrEP) significantly reduces the risk of HIV acquisition in adults. Its use was expanded to include youth over 35 kg by the U.S. Food and Drug Administration in 2018. However, PrEP uptake remains low among adolescents. Prescriber-identified barriers include lack of experience, concerns about safety, unfamiliarity with follow-up guidelines, and costs. This article provides an overview of PrEP for youth in Canada, and its associated safety and side effect profiles. Hypothetical case vignettes highlight some of the many demographics of youth who could benefit from PrEP. We present a novel flow diagram that explains the baseline workup, prescribing guidelines, and follow-up recommendations in the Canadian context. Additional counselling points highlight some of the key discussions that should be elicited when prescribing PrEP.

The HIV care cascade is an indicators-framework used to assess achievement of HIV clinical targets including HIV diagnosis, HIV care initiation and retention, initiation of antiretroviral therapy, and attainment of viral suppression for people living with HIV.The HIV Care Cascade Research Development Team at the CIHR Canadian HIV Trials Network Clinical Care and Management Core hosted a two-day virtual workshop to present HIV care cascade data collected nationally from local and provincial clinical settings and national cohort studies. The article summarizes the workshop presentations including the indicators used and available findings and presents the discussed challenges and recommendations.Identified challenges included (1) inconsistent HIV care cascade indicator definitions, (2) variability between the use of nested UNAIDS's targets and HIV care cascade indicators, (3) variable analytic approaches based on differing data sources, (4) reporting difficulties in some regions due to a lack of integration across data platforms, (5) lack of robust data on the first stage of the care cascade at the sub-national level, and (6) inability to integrate key socio-demographic data to estimate population-specific care cascade shortfalls.There were four recommendations: standardization of HIV care cascade indicators and analyses, additional funding for HIV care cascade data collection, database maintenance and analyses at all levels, qualitative interviews and case studies characterizing the stories behind the care cascade findings, and employing targeted positive-action programs to increase engagement of key populations in each HIV care cascade stage.La cascade des soins du VIH est un cadre d’indicateurs utilisé pour évaluer l’atteinte des cibles cliniques du VIH, y compris le diagnostic, le début et le maintien des soins, le début du traitement antirétroviral et l’obtention de la suppression virale chez les personnes qui vivent avec le VIH.L’équipe de développement de la recherche sur la cascade des soins du VIH située au noyau de perfectionnement de la gestion clinique du Réseau canadien pour les essais VIH des IRSC a organisé un atelier virtuel de deux jours pour présenter les données sur la cascade des soins du VIH amassées dans les milieux cliniques locaux et provinciaux et les études de cohorte de tout le pays. L’article résume les présentations d’ateliers, y compris les indicateurs utilisés et les observations disponibles, et présente les défis et recommandations abordés.Les défis mis en évidence incluaient 1) les définitions hétérogènes des indicateurs de la cascade des soins sur le VIH, 2) la variabilité entre l’utilisation des cibles d’ONUSIDA imbriquées et les indicateurs de cascade des soins du VIH, 3) des approches analytiques variables d’après diverses sources de données, 4) la déclaration des difficultés dans certaines régions à cause de l’absence d’intégration entre les plateformes de données, 5) l’absence de données vigoureuses sur la première étape de la cascade des soins infranationaux et 6) l’incapacité d’intégrer les principales données sociodémographiques pour évaluer les écueils de la cascade des soins populationnels.Quatre recommandations ont été formulées : la standardisation des indicateurs et des analyses de la cascade des soins du VIH, le financement supplémentaire de la collecte de la cascade des soins du VIH, l’entretien des bases de données et les analyses à tous les échelons, les entrevues qualitatives et les études de cas qui caractérisent les histoires qui se cachent derrière les observations tirées de la cascade des soins et le recours à des programmes d’action positive ciblés pour accroître la participation de populations clés à chaque étape de la cascade des soins du VIH.

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

Summary Background Acute flaccid myelitis (AFM) is characterised by rapid onset of limb weakness with spinal cord grey-matter abnormalities on MRI scan. We aimed to assess whether detection of enterovirus in respiratory or other specimens can help predict prognosis in children with AFM. Methods In this nationwide, longitudinal study, we evaluated the significance of detection of enterovirus in any sample in predicting outcomes in a cohort of Canadian children younger than 18 years presenting with AFM to tertiary paediatric hospitals in Canada in 2014 and 2018. All patients fulfilled the 2015 US Centers for Disease Control and Prevention case definition for definite AFM or probable AFM. Clinical data, laboratory findings, treatment, and neuroimaging results were collected (follow up period up to 5 years). We assessed neurological function and motor outcomes using Kurtzke's Expanded Disability Status Scale (EDSS) and a Weakest Limb Score. Findings 58 children with AFM (median age 5·1 years, IQR 3·8–8·3) were identified across five of Canada's ten provinces and three territories. 25 (43%) children had enterovirus detected in at least one specimen: 16 (64%) with EV-D68, two (8%) with EV-A71, two (8%) with coxsackievirus, 10 (40%) with untyped enterovirus. Children who were enterovirus positive were more likely than those that were negative to have had quadriparesis (12 [48%] of 25 vs four [13%] of 30; p=0·028), bulbar weakness (11 [44%] of 25 vs two [7%] of 30; p=0·028), bowel or bladder dysfunction (14 [56%] of 25 vs seven [23%] of 30; p=0·040), cardiovascular instability (nine [36%] of 25 vs one [3%] of 30; p=0·028), and were more likely to require intensive care unit admission (13 [52%] of 25 vs 5 [17%] of 30; p=0·028). On MRI, most children who were enterovirus positive showed brainstem pontine lesions (14 [61%] of 23), while other MRI parameters did not correlate with enterovirus status. Median EDSS of enterovirus positive (EV+) and enterovirus negative (EV–) groups was significantly different at all timepoints: baseline (EDSS 8·5, IQR 4·1–9·5 vs EDSS 4·0, IQR 3·0–6·0; p=0·0067), 3 months (EDSS 4·0, IQR 3·0–7·4 vs EDSS 3·0, IQR 1·5–4·3; p=0·0067), 6 months (EDSS 3·5, IQR 3·0–7·0 vs EDSS 3·0, IQR 1·0–4·0; p=0·029), and 12 months (EDSS 3·0, IQR 3·0–6·9 vs EDSS 2·5 IQR 0·3–3·0; p=0·0067). Kaplan-Meier survival analysis of a subgroup of patients showed significantly poorer motor recovery among children who tested positive for enterovirus than for those who tested negative (p=0·037). Interpretation Detection of enterovirus in specimens from non-sterile sites at presentation correlated with more severe acute motor weakness, worse overall outcomes and poorer trajectory for motor recovery. These results have implications for rehabilitation planning as well as counselling of families of children with these disorders. The findings of this study support the need for early testing for enterovirus in non-CNS sites in all cases of AFM. Funding None.

Uganda adapted its policy for prevention of vertical transmission (VT) of HIV transmission as the World Health Organization released Options A, B and B+. We assessed trends in diagnostic testing, breastfeeding practices, maternal and infant antiretroviral therapy (ART), mortality, VT and HIV-free survival (HFS) among Ugandan infants born to women living with HIV during this period of successive guideline changes.This is is a retrospective observational study of infants attending early infant diagnosis clinics at two Ugandan hospitals.A total of 1885 infants (48% female) were managed from 2009 to 2017. DNA polymerase chain reaction (PCR) for early infant diagnosis was performed on 1719 infants (92%, one or more PCR tests) and 676 infants (36%, two PCR tests). HIV serology was performed on 90 infants (4.8%). Testing increased over the study period but remained suboptimal, due to high loss to follow-up (LTFU). A total of 93% of infants were breastfed, for a median of 9.5 months. The duration of breast milk exposure increased over the study period, consistent with guidelines that increasingly encouraged breastfeeding. Nine cases (0.48%) of suspected breast milk transmission were observed. The use of ART increased significantly over the study period. Mortality (3.5%, 2.7% and 1.1%; p = 0.0076) and VT (17%, 12% and 7.4%; p 0.0001) decreased over the study period (2008-2010, 2011-2012 and 2013-2017, respectively). LTFU values were 31%, 49% and 59% at 6, 12 and 18 months of age, respectively, with only modest improvements over time. HFS could only be conclusively documented in 532 infants (28%) because of LTFU.From 2009 to 2017, outcomes improved among HIV-exposed infants in Uganda. LTFU remains a barrier to optimal care.

Objectives Combination antiretroviral therapy has largely restored the lifespan of persons living with HIV. Data suggest early comorbidities of aging in this population. Past studies focused on men; limited data exist regarding the prevalence of dyslipidaemia in women living with HIV (WLWH). We investigated the prevalence of cardiometabolic abnormalities among WLWH and HIV-negative women in the Children and Women: Antiretrovirals and Markers of Aging (CARMA) cohort, and their relationships to cellular aging markers. Methods We conducted a cross-sectional analysis of nonpregnant female patients (156 WLWH and 133 HIV-negative controls, aged 12-69 years) enrolled in CARMA between 2013 and 2017. The Framingham risk score (FRS) and the prevalences of hypertension, diabetes, metabolic syndrome and dyslipideamia were determined using self-report, anthropometrics, chart review and laboratory data. Cellular aging was determined by assessing leukocyte telomere length and blood mitochondrial DNA content. Diagnoses were based on current Canadian guidelines and definitions. Results HIV-infected status was associated with dyslipidaemia [odds ratio (OR) 2.89; 95% confidence interval (CI) 1.69-5.01], but not diabetes, higher FRS, hypertension or metabolic syndrome. The median age was 43.5 [interquartile range (IQR) 36.8-50.9] years in WLWH and 46.2 (IQR 30.3-54.9) years in HIV-negative controls. WLWH were less likely to be menopausal or use alcohol, and more often had hepatitis C virus infection or a current or past smoking history. Lower mitochondrial DNA content was associated with metabolic syndrome; no other associations were noted between cardiometabolic abnormalities and markers of cellular aging. Conclusions Despite their relatively young age, almost two-thirds of WLWH had dyslipidaemia, a significantly greater proportion than in controls. Strategies to address dyslipidaemia and decrease smoking rates may improve long-term outcomes among WLWH.

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.

BACKGROUND Systemic inflammation, platelet dysfunction, and endothelial activation persist in people living with HIV despite sustained virologic suppression (SVS) with combined antiretroviral therapy (cART) and may lead to complications such as atherosclerosis and cardiovascular disease. Angiopoietin-1 (Ang-1) is a key regulator of angiogenesis and endothelial activation and has been studied as an objective biomarker in disease states such as atherosclerosis, sepsis, and severe malaria. SETTING Eight pediatric HIV care centers across Canada. METHODS Cross-sectional study of 61 children living with vertically acquired HIV on cART with undetectable RNA viral load. Plasma levels of Ang-1 were measured by ELISA and analyzed in relation to clinical characteristics abstracted from medical records. RESULTS Ang-1 levels were directly correlated with clinical indices of virologic control: cumulative proportion of life on effective cART (ρ = +0.35, P = 0.0078) and cumulative proportion of life with SVS (ρ = +0.36, P = 0.0049). Furthermore, higher Ang-1 levels were associated with younger age at SVS (ρ = -0.56, P < 0.0001). These associations remained statistically significant in multivariable linear regression models adjusting for potential confounders (P < 0.05 for all associations). CONCLUSIONS Early effective cART and SVS were associated with higher Ang-1 levels in children living with vertically acquired HIV-1.

Using baseline data from a community-collaborative cohort of women living with HIV in Canada, we assessed the prevalence and correlates of help-seeking among 1,057 women who reported experiencing violence in adulthood (≥16 years). After violence, 447 (42%) sought help, while 610 (58%) did not. Frequently accessed supports included health care providers ( n = 313, 70%), family/friends ( n = 244, 55%), and non-HIV community organizations ( n = 235, 53%). All accessed supports were perceived as helpful. Independent correlates of help-seeking included reporting a previous mental health diagnosis, a history of injection drug use, experiencing childhood violence, and experiencing sexism. We discuss considerations for better supporting women who experience violence.

Background Lyme disease (LD) is caused by the tick-borne bacterium Borrelia burgdorferi. Over the past ten years, robust local public health data indicates that the incidence of LD has increased significantly in the eastern region of Ontario due to the spread of its vector, the blacklegged tick. As a result, we have seen an increase in the number of cases of LD in children at our tertiary paediatric centre, at all stages of infection. Familiarity with Lyme disease is important as incidence increases. We sought to characterize the cases at our centre. Objectives To describe the epidemiology of LD in children at our centre from 2009-2018, as well as the variety of clinical presentations of paediatric LD. Design/Methods We completed a retrospective chart review from 2009-2018 of all cases admitted or seen in the Infectious Disease (ID) clinic or the Emergency Department (ED) with a diagnosis of LD. Demographic, clinical and laboratory data were collected, including geographic location where infection occurred and resource utilization. We used descriptive statistics to describe cases and comparative statistics to determine changes in number of cases over time. Results There were 171 LD cases managed at our centre during this period. Mean age was 7.4 (SD 4.5) years, 89 (52.0%) were male. The annual number of cases from 2009 - 2018 increased from 1 to 44 and peaked in 2017 (47 cases). The highest number of cases occurred among children Early and late disseminated cases occurred more commonly in the summer and accounted for the majority of admissions. These included neurologic Lyme (lymphocytic meningitis [2, 1.2%], polyneuropathy [1, 0.6%], cranial nerve palsy [13, 7.6%]), Lyme carditis (5, 2.9%), and Lyme arthritis (29, 17.0%). There were 133 (77.8%) patients managed in ED, 66 (38.6%) in the ID clinic and 17 (9.9%) in the inpatient ward; median length of stay was 6 (IQR 5, 9) days, with a range of 1 to 30 days. The most common geographic locations of infection acquisition were Ottawa (120 cases, 71.0%) and Kingston (26, 15.4%). Conclusion Cases of LD managed at our paediatric centre have increased in keeping with population trends, with all LD stages experienced. Severe cases of meningitis, carditis, and arthritis resulted in hospitalization, with increasing numbers over the study period.

Background: The relative contribution of viruses to central nervous system (CNS) infections in young infants is not clear. For viral CNS infections, there are limited data on features that suggest HSV etiology or on predictors of unfavorable outcome. Methods: In this cross-sectional retrospective study, seven centers from the Pediatric Investigators Collaborative Network on Infections in Canada identified infants

BackgroundCombination antiretroviral therapy (cART) during pregnancy prevents vertical transmission, but many antiretrovirals cross the placenta and several can affect mitochondria. Exposure to maternal human immunodeficiency virus (HIV) and/or cART could have long-term effects on children who are HIV exposed and uninfected (CHEU). Our objective was to compare blood mitochondrial DNA (mtDNA) content in CHEU and children who are HIV unexposed and uninfected (CHUU), at birth and in early life.MethodsWhole-blood mtDNA content at birth and in early life (age 0–3 years) was compared cross-sectionally between CHEU and CHUU. Longitudinal changes in mtDNA content among CHEU was also evaluated.ResultsAt birth, CHEU status and younger gestational age were associated with higher mtDNA content. These remained independently associated with mtDNA content in multivariable analyses, whether considering all infants, or only those born at term. Longitudinally, CHEU mtDNA levels remained unchanged during the first 6 months of life, and gradually declined thereafter. A separate age- and sex-matched cross-sectional analysis (in 214 CHEU and 214 CHUU) illustrates that the difference in mtDNA between the groups remains detectable throughout the first 3 years of life.ConclusionThe persistently elevated blood mtDNA content observed among CHEU represents a long-term effect, possibly resulting from in utero stresses related to maternal HIV and/or cART. The clinical impact of altered mtDNA levels is unclear.

Background The relative contribution of viruses to central nervous system (CNS) infections in young infants is not clear. For viral CNS infections, there are limited data on features that suggest HSV etiology or on predictors of unfavorable outcome. Methods In this cross-sectional retrospective study, seven centers from the Pediatric Investigators Collaborative Network on Infections in Canada identified infants Results Of 174 CNS infections with a proven etiology, EV accounted for 103 (59%) and HSV for 7 (4%). All HSV cases and 41 (40%) EV cases presented before 21 days of age. Four HSV cases (57%) and 5 EV cases (5%) had seizures. Three (43%) HSV and 23 (23%) EV cases lacked cerebrospinal fluid (CSF) pleocytosis. HSV cases were more likely to require ICU admission (p = 0.010), present with seizures (p = 0.031) and have extra-CNS disease (p p = 0.002). Conclusions Viruses accounted for approximately two-thirds of proven CNS infections in the first 90 days of life. Empiric therapy for HSV should be considered in suspected CNS infections in the first 21 days even in the absence of CSF pleocytosis unless CSF parameters are suggestive of bacterial meningitis. Neurodevelopmental follow-up should be considered in infants whose course of illness is complicated by seizures.

BACKGROUND: Vertical HIV transmission has declined in Canada, but missed opportunities for prevention continue to occur. We sought to determine the adequacy, and changes over time in adequacy, of uptake of maternal and neonatal antiretroviral therapy for the prevention of vertical HIV transmission, and to determine the vertical transmission rate over time and according to adequacy of antenatal antiretroviral therapy during the combination antiretroviral therapy era in Canada. METHODS: The Canadian Perinatal HIV Surveillance Program collects data annually through retrospective chart review concerning HIV-infected women and their infants. We determined receipt of adequate antiretroviral treatment (antenatal combination antiretroviral treatment for ≥ 4 wk, intrapartum intravenous zidovudine treatment and 4-6 wk of infant oral zidovudine treatment) and predictors of inadequate antenatal combination antiretroviral therapy (none or < 4 wk) in Canada in 1997-2016. RESULTS: We identified 3785 mother-infant pairs. Uptake of 4 weeks or more of antenatal combination antiretroviral therapy increased over time across all provinces/territories and regardless of maternal race/ethnicity or risk category (p < 0.001). During 2011-2016, 92 women (6.5%) received no or less than 4 weeks of antenatal combination antiretroviral therapy, 146 women (10.7%) received no intrapartum zidovudine treatment, and 43 infants (3.1%) received less than 4 weeks of zidovudine treatment. In multivariate analysis restricted to 2011-2016, higher uptake of adequate antenatal combination antiretroviral therapy was seen among black women than among Indigenous (odds ratio [OR] 2.99, 95% confidence interval [CI] 1.23-7.26) or white (OR 1.87, 95% CI 0.99-1.27) women and in British Columbia/Yukon Territory than in Alberta (OR 3.31, 95% CI 1.06-10.32), Ontario (OR 3.16, 95% CI 1.08-9.26) or Quebec (OR 3.44, 95% CI 1.09-10.84). Among the 14 vertical HIV transmission events during 2011-2016 (vertical transmission rate 1.0%), maternal HIV infection was diagnosed before the onset of labour in 5 cases, and only 2 women received adequate antenatal combination antiretroviral therapy. INTERPRETATION: Efforts to improve timely access to care, HIV screening and treatment for all women, combined with enhanced resources targeting populations at increased risk for HIV infection, will be needed if vertical HIV transmission is to be eliminated in Canada.

Background: Associations between HIV-related stigma and reduced antiretroviral therapy (ART) adherence are widely established, yet the mechanisms accounting for this relationship are underexplored. There has been less attention to HIV-related stigma and its associations with ART initiation and current ART use. We examined pathways from HIV-related stigma to ART initiation, current ART use, and ART adherence among women living with HIV in Canada. Methods: We used baseline survey data from a national cohort of women living with HIV in Canada (n = 1425). Structural equation modeling using weighted least squares estimation methods was conducted to test the direct effects of HIV-related stigma dimensions (personalized, negative self-image, and public attitudes) on ART initiation, current ART use, and 90% ART adherence, and indirect effects through depression and HIV disclosure concerns, adjusting for sociodemographic factors. Results: In the final model, the direct paths from personalized stigma to ART initiation (β = −0.104, P < 0.05) and current ART use (β = −0.142, P < 0.01), and negative self-image to ART initiation (β = −0.113, P < 0.01) were significant, accounting for the mediation effects of depression and HIV disclosure concerns. Depression mediated the pathways from personalized stigma to ART adherence, and negative self-image to current ART use and ART adherence. Final model fit indices suggest that the model fit the data well [χ2(25) = 90.251, P < 0.001; comparative fit index = 0.945; root-mean-square error of approximation = 0.044]. Conclusions: HIV-related stigma is associated with reduced likelihood of ART initiation and current ART use, and suboptimal ART adherence. To optimize the benefit of ART among women living with HIV, interventions should reduce HIV-related stigma and address depression.

Background Women comprise nearly one-quarter of people living with human immunodeficiency virus (HIV) in Canada. Compared with men, women living with HIV experience inequities in HIV care and health outcomes, prompting a need for gendered and tailored approaches to HIV care. Method Peer and academic researchers from the Canadian HIV Women's Sexual and Reproductive Health Cohort Study conducted focus groups to understand women's experience of seeking care, with the purpose of identifying key characteristics that define a women-centered approach to HIV care. Eleven focus groups were conducted with 77 women living with HIV across Quebec, Ontario, and British Columbia, Canada. Results Women envisioned three central characteristics of women-centered HIV care, including i) coordinated and integrated services that address both HIV and women's health care priorities, and protect against exclusion from care due to HIV-related stigma, ii) care that recognizes and responds to structural barriers that limit women's access to care, such as violence, poverty, motherhood, HIV-related stigma, and challenges to safe disclosure, and iii) care that fosters peer support and peer leadership in its design and delivery to honor the diversity of women's experiences, overcome women's isolation, and prioritize women's ownership over the decisions that affect their lives. Conclusion Despite advances in HIV treatment and care, the current care landscape is inadequate to meet women's comprehensive care needs. A women-centered approach to HIV care, as envisioned by women living with HIV, is central to guiding policy and practice to improve care and outcomes for women living with HIV in Canada.

Transitioning from pediatric to adult care is a complicated process for youth with chronic illnesses. This study elucidates the unique factors affecting transition preparedness and perception of adult HIV care among a cohort of young women with HIV. Between 2013 and 2015, 48 women with HIV, who had experience with pediatric HIV care, were enrolled in a large Canadian cohort study. Variables were self-reported during peer-administered surveys. Only 60% reported feeling prepared for transition. Having never had contact with child protection services ( P = .049), never been in foster care ( P = .011), never been in a group home ( P = .036), reporting a higher current CD4 count ( P = .033), and reporting a younger ideal age for transition ( P = .041) were associated with transition preparedness. Eighty-four percent reported equivalent or better HIV care following transition. Correlates of equivalent/better care following transition included lower personal income ( P = .023), higher CD4 count ( P = .021), care by an adult infectious diseases specialist ( P = .002), and transition preparedness ( P = .005). Our findings highlight the importance of adequate transition preparation and its effect on perception of care following transition.

Leukocyte telomere length (LTL) and whole blood mitochondrial DNA (WB mtDNA) content are aging markers impacted by chronic diseases such as human immunodeficiency virus (HIV) infection. We characterized the relationship between these two markers in 312 women ≥12 years of age living with HIV and 300 HIV-negative controls. We found no relationship between the two markers cross-sectionally. In multivariable models, age, ethnicity, HIV, and tobacco smoking were independently associated with shorter LTL, and the former three with lower WB mtDNA. Longitudinally, among a subgroup of 228 HIV participants and 68 HIV-negative controls with ≥2 biospecimens ≥1 year apart, an inverted pattern was observed between the rates of change in LTL and WB mtDNA content per year, whereby faster decline of one was associated with the preservation of the other. Furthermore, if HIV viral control was not maintained between visits, increased rates of both LTL attrition and WB mtDNA loss were observed. We describe a novel relationship between two established aging markers, whereby rates of change in LTL and WB mtDNA are inversely related. Our findings highlight the importance of maintaining HIV viral control, the complementary longitudinal relationship between the two markers, and the need to consider both in aging studies.

Background The relative contribution of viruses to central nervous system (CNS) infections in young infants is not clear. For viral CNS infections, there are limited data on features that suggest HSV etiology or that are predictors of unfavorable outcome. Methods In this cross-sectional study, the Pediatric Investigators Collaborative Network on Infections in Canada identified infants

Background: Acute flaccid myelitis (AFM) is characterized by rapid onset of limb weakness with spinal cord grey matter abnormalities on magnetic resonance imaging (MRI). It is unclear whether detection of enterovirus (EV) in respiratory or other specimens can help predict prognosis in children with AFM. Methods: In this nationwide longitudinal study, we evaluated the significance of peripheral detection of EV in predicting outcomes in a cohort of Canadian children presenting with AFM in 2014 and 2018. Clinical data, laboratory findings, treatment, and neuroimaging were collected (follow up period up to five years). We assessed neurologic function and motor outcomes using Kurtzke’s Expanded Disability Status Scale (EDSS) and a “weakest limb score” (WLS). Findings: 58 children with AFM (median 5⋅1 years [IQR 3⋅8-8⋅3]) were identified across five provinces. Twenty-two (39%) children had detectable EV in at least one specimen: EV-D68 in 14 (64%), EV-A71 in two (9%), coxsackievirus, and untyped EV in eight (36%). Children with EV detected were more likely to have had quadriparesis (55% vs. 12%, p=0⋅005), bulbar weakness (50% vs 6%, p=0⋅004), bowel/bladder dysfunction (59% vs 24%, p=0⋅033), cardiovascular instability (36% vs 6%, p=0⋅032), and were more likely to require intensive care unit admission (59% vs. 15%, p 0⋅005). On MRI, most children with EV positivity showed brainstem pontine lesions (59%), while other MRI parameters did not correlate with EV status. EDSS of EV+ and EV- groups was significantly different at baseline (median 8⋅5 [interquartile range, IQR 4-9⋅5] vs. 4⋅8 [IQR 3⋅4-7⋅1], p=0⋅012) and 12 months (median 3 [IQR 3-7] vs. 3 [IQR 2-3], p=0⋅036). Kaplan-Meier survival analysis of a subgroup of patients showed significantly poorer motor recovery among children with detected EV than those tested negative (p=0⋅032). Interpretation: Detection of EV in specimens from non-sterile sites at presentation correlated with more severe acute motor weakness, worse overall outcomes and poorer trajectory for motor recovery. Funding Statement: None. Declaration of Interests: EAY reports grants from Canadian Network of MS Clinics during the conduct of the study; grants from Biogen, grants from NMSS, grants from CMSC, grants from 18 MSSC/MS Foundation, grants from OIRM, grants from SCN, grants from SickKids Foundation, personal fees from ACI, personal fees from US FDA, grants from CBMH, grants from TEVA, grants from Guthy Jackson Foundation, personal fees from Juno, outside the submitted work. All other authors have no conflict of interest to disclose. Ethics Approval Statement: This study was approved by the research ethics board/committee of all above-listed participating institutions. Informed consents were obtained according to individual institutional requirements.

Background Adolescent tetanus, diphtheria and pertussis (Tdap) immunization helps prevent pertussis infection. Timing of Tdap receipt represents an important facet of successful adolescent pertussis immunization. Potential strategies for timing of vaccine administration are each associated with different benefits – including disease prevention – and costs. The objective of this study was to assess the cost-utility of adolescent pertussis immunization strategies in Canada. Methods A cost-utility analysis was conducted using a pertussis disease history-simulating Markov model, with adolescents (beginning at age 10 years) as the cohort of interest. The model assessed three Tdap vaccination strategies: (1) immunization of 10 year olds, (2) removal of adolescent vaccination, and (3) immunization of 14 year olds (status quo). The analysis was conducted from a healthcare payer perspective and used a lifetime time horizon. Primary outcomes included life years, quality-adjusted life years (QALYs), health system costs, and an incremental cost-effectiveness ratio (ICER). Costs and outcomes were discounted at 1.5 percent annually. Deterministic and probabilistic sensitivity analyses were performed to assess parameter uncertainty. Results The current recommended adolescent immunization strategy (at age 14) resulted in an average of 40.4432 expected QALYs and $26.28 per individual. This strategy was dominated by immunization at 10 years and no immunization. Compared to no immunization, immunizing adolescents at age 10 had an ICER of $74,899 per QALY. Results were most sensitive to the incidence of pertussis and the utility of moderate or severe pertussis. At a cost-effectiveness threshold of $50,000/QALY, removal of adolescent vaccination represented the most cost-effective strategy in 78% of simulations. Conclusion Analysis assumes a policy context where immunization of pregnant women is recommended. Findings suggest that alternate adolescent Tdap vaccine strategies – either immunization of 10 year olds, or removal of the adolescent vaccine – are more cost-effective than the current practice of immunizing 14 year olds.

BACKGROUND: Herpes simplex virus (HSV) and enterovirus (EV) are important causes of central nervous system (CNS) infections in young infants. Though long-term morbidity has been linked to HSV, there is still limited data on outcomes of other viral CNS infections in young infants. OBJECTIVES: 1) Conduct a descriptive analysis of viral CNS infections in infants 0.05). CONCLUSION: Among infants

We describe the presenting features and long-term outcome of an unusual cluster of pediatric acute flaccid paralysis cases that occurred in Canada during the 2014 enterovirus D68 outbreak. Children (n = 25; median age 7.8 years) presenting to Canadian centers between July 1 and October 31, 2014, and who met diagnostic criteria for acute flaccid paralysis were evaluated retrospectively. The predominant presenting features included prodromal respiratory illness (n = 22), cerebrospinal fluid lymphocytic pleocytosis (n = 18), pain in neck/back (n = 14) and extremities (n = 10), bowel/bladder dysfunction (n = 9), focal central gray matter lesions found in all regions of the spinal cord within the cohort (n = 16), brain stem lesions (n = 8), and bulbar symptoms (n = 5). Enterovirus D68 was detectable in nasopharyngeal specimens (n = 7) but not in cerebrospinal fluid. Acute therapies (corticosteroids, intravenous immunoglobulins, plasmapheresis) were well tolerated with few side effects. Fourteen of 16 patients who were followed beyond 12 months post onset had neurologic deficits but showed ongoing clinical improvement and motor recovery.

We report a case of therapeutic drug monitoring guided raltegravir use for the prevention of vertical HIV transmission in a premature neonate born to a woman living with perinatally acquired HIV and documented resistance to multiple HIV drugs. Maternal viral load was above 1,000 copies/ml at delivery. This case demonstrates delayed raltegravir elimination in a neonate born at 33 weeks gestational age and a need for less frequent raltegravir dosing than is used in older infants and children.

We evaluated quadrivalent human papillomavirus vaccine seroresponses among 35 girls living with HIV (9-13 years of ages) and compared with data on girls without HIV, as part of a subgroup analysis. The quadrivalent human papillomavirus vaccine was safe and well tolerated. However, antibody response was significantly lower in girls living with HIV relative to girls without HIV. HIV virologic suppression predicted better antibody response.

Background The Early Pediatric Initiation Canada Child Cure Cohort (EPIC4) study is a prospective, multicenter, Canadian cohort study investigating human immunodeficiency virus–1 (HIV-1) reservoirs, chronic inflammation, and immune responses in children with perinatally acquired HIV-1 infection. The focus of this report is HIV-1 reservoirs and correlates in the peripheral blood of children who achieved sustained virologic suppression (SVS) for ≥5 years. Methods HIV-1 reservoirs were determined by measuring HIV-1 DNA in peripheral blood mononuclear cells and inducible cell-free HIV-1 RNA in CD4+ T-cells by a prostratin analogue stimulation assay. HIV serology was quantified by signal-to-cutoff ratio (S/CO). Results Of 228 enrolled participants, 69 achieved SVS for ≥5 years. HIV-1 DNA, inducible cell-free HIV-1 RNA, and S/COs correlated directly with the age of effective combination antiretroviral therapy (cART) initiation (P < .001, P = .036, and P < .001, respectively) and age when SVS was achieved (P = .002, P = .038, and P < .001, respectively) and inversely with the proportion of life spent on effective cART (P < .001, P = .01, and P < .001, respectively) and proportion of life spent with SVS (P < .001, P = .079, and P < .001, respectively). Inducible cell-free HIV-1 RNA correlated with HIV-1 DNA, most particularly in children with SVS, without virologic blips, that was achieved with the first cART regimen initiated prior to 6 months of age (rho = 0.74; P = .037) or later (rho = 0.87; P < .001). S/COs correlated with HIV-1 DNA (P = .003), but less so with inducible cell-free HIV-1 RNA (P = .09). Conclusions The prostratin analogue stimulation assay, with its lower blood volume requirement, could be a valuable method for evaluating inducible HIV-1 reservoirs in children. Standard commercial HIV serology may be a practical initial indirect measure of reservoir size in the peripheral blood of children with perinatally acquired HIV-1 infection.

BACKGROUND. The goal of antiretroviral therapy (ART) is to suppress HIV-1 replication and reconstitute CD4(+) T cells. Here, we report on HIV-infected individuals who had a paradoxical decline in CD4(+) T cells despite ART-mediated suppression of plasma HIV-1 load (pVL). We defined such an immunological outcome as extreme immune decline (EXID). METHODS. EXID’s clinical and immunological characteristics were compared to immunological responders (IRs), immunological nonresponders (INRs), healthy controls (HCs), and idiopathic CD4(+) lymphopenia (ICL) patients. T cell immunophenotyping and assembly/activation of inflammasomes were evaluated by flow cytometry. PBMC transcriptome analysis and genetic screening for pathogenic variants were performed. Levels of cytokines/chemokines were measured by electrochemiluminescence. Luciferase immunoprecipitation system and NK-mediated antibody-dependent cellular cytotoxicity (ADCC) assays were used to identify anti-lymphocyte autoantibodies. RESULTS. EXIDs were infected with non-B HIV-1 subtypes and after 192 weeks of consistent ART-mediated pVL suppression had a median CD4(+) decrease of 157 cells/μl, compared with CD4(+) increases of 193 cells/μl and 427 cells/μl in INR and IR, respectively. EXID had reduced naive CD4(+) T cells, but similar proportions of cycling CD4(+) T cells and HLA-DR(+)CD38(+)CD8(+) T cells compared with IR and INR. Levels of inflammatory cytokines were also similar in EXID and INR, but the IL-7 axis was profoundly perturbed compared with HC, IR, INR, and ICL. Genes involved in T cell and monocyte/macrophage function, autophagy, and cell migration were differentially expressed in EXID. Two of the 5 EXIDs had autoantibodies causing ADCC, while 2 different EXIDs had an increased inflammasome/caspase-1 activation despite consistently ART-suppressed pVL. CONCLUSIONS. EXID is a distinct immunological outcome compared with previously described INR. Anti–CD4(+) T cell autoantibodies and aberrant inflammasome/caspase-1 activation despite suppressed HIV-1 viremia are among the mechanisms responsible for EXID.

Long-term outcomes of perinatal exposure to maternal antiretroviral therapy in HIV-exposed uninfected (HEU) children are unknown. However, both HIV antiretroviral therapy and autism spectrum disorder (ASD) have been associated with mitochondrial alterations. Leukocyte mitochondrial DNA (mtDNA) content can serve as a marker for mitochondrial dysfunction. In this cross-sectional, nested case-control study, HEU children with ASD were matched approximately 1:3 on age, sex, and ethnicity to HEU children without ASD, HIV-unexposed uninfected (HUU) controls, and HUU children with ASD. Leukocyte mtDNA content was measured using quantitative PCR. Among 299 HEU in this study, 14 (4.7%) were diagnosed with ASD, which is higher than the general population prevalence estimates. HEU children without ASD and HUU children with ASD had higher mtDNA content than HUU controls. HEU children with ASD had significantly higher mtDNA content than all other study groups. Our results suggest a clear association between elevated leukocyte mtDNA content and both HEU and ASD status. This may implicate mitochondrial dysfunction as a contributor to the high ASD prevalence observed in our cohort.

Introduction Heat‐stable lopinavir/ritonavir (LPV/r) oral pellets were developed to overcome challenges with administration and storage experienced with previously available tablet and syrup forms of LPV/r prescribed to paediatric HIV patients. We report on the adoption of LPV/r pellets for infants living with HIV in the public sector antiretroviral therapy (ART) programme in Zimbabwe. Methods Infants aged three months to three years who had been prescribed a LPV/r‐based regimen (including ART‐naïve patients) in fourteen facilities across the country were eligible to receive the pellets. Caregivers were counselled on the new formulation and provided with administration guides. A caregiver questionnaire was administered three to four months after the child initiated on pellets. Data were also extracted from patient ART records. Results and discussion One hundred and fifty‐seven children were enrolled (median age: 21 months; interquartile range 11.8 to 29.4). Survey data from 74 caregivers were included for analysis. Eighty‐one per cent of the caregivers preferred pellets while 19% preferred the syrup formulation. Eighty‐nine per cent assessed their child's response to taking the pellets as good or very good. Overall, 46% did not report any challenges while 54% reported one or more challenges with using the pellets. Difficulties with administration included: poor taste (36%; 26 participants); swallowing pellets (16%; 12 participants); finishing the dose (14%; 10 participants); and opening the capsule (10%; seven participants). Caregivers who were not confident to instruct others on pellet administration were 5.64 (95% confidence interval 1.45 to 21.95, p = 0.013) times as likely to experience a challenge. Conclusions A large proportion of caregivers preferred pellets to other formulations of LPV/r and reported a good response to pellets; however, they also reported challenges with administration. Counselling should focus on ensuring that caregivers can confidently administer pellets and are able to instruct others, to ensure high uptake and good adherence to treatment. LPV/r pellets may be an acceptable substitute for other available forms of LPV/r for eligible children under three years if they are currently on or in need of LPV/r‐containing regimens; however, challenges with administration still highlight the need for improved drug formulations for paediatric ART patients.

Background On behalf of the Public Health Agency of Canada, the Committee to Advise on Tropical Medicine and Travel (CATMAT) developed the Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers for Canadian health care providers who are preparing patients for travel to malaria-endemic areas and treating travellers who have returned ill. These recommendations aim to achieve appropriate diagnosis and management of malaria, a disease that is still uncommon in Canada. Objective To provide recommendations on the appropriate diagnosis and treatment of malaria. Methods CATMAT reviewed all major sources of information on malaria diagnosis and treatment, as well as recent research and national and international epidemiological data, to tailor guidelines to the Canadian context. The evidence-based medicine recommendations were developed with associated rating scales for the strength and quality of the evidence. Recommendations Malarial management depends on rapid identification of the disease, as well as identification of the malaria species and level of parasitemia. Microscopic identification of blood samples is both rapid and accurate but can be done only by trained laboratory technicians. Rapid diagnostic tests are widely available, are simple to use and do not require specialized laboratory equipment or training; however, they do not provide the level of parasitemia and do require verification. Polymerase chain reaction (PCR), although still limited in availability, is emerging as the gold standard for high sensitivity and specificity in identifying the species.