Increased risk of hospitalization among children who were HIV-exposed and uninfected compared to population controls.

OBJECTIVES: While studies have demonstrated increased morbidity and mortality risk in infancy among children who are HIV-exposed and uninfected (CHEU), longitudinal data are limited. The objective of this study was to assess long-term risk of hospitalization among CHEU compared to children who are HIV-unexposed and uninfected (CHUU), and determine risk factors for hospitalization among CHEU. DESIGN: Longitudinal cohort study (1988-2015) linking the Centre maternel et infantile sur le SIDA cohort (Montreal, Quebec) to administrative data from the Régie de l'assurance maladie du Québec (RAMQ), a universal health insurance provider in the province of Quebec. METHODS: CHEU from the CMIS cohort were matched 1:3 by age, sex and postal code with CHUU controls from the RAMQ database. Incidence and causes of hospitalization between CHEU and CHUU were compared using Poisson regression. RESULTS: 726 CHEU were matched to 2178 CHUU. Risk of first hospitalization was significantly higher among CHEU at 1 year (IRR 2.22, [1.86-2.66]), 5 years (IRR 1.62, [1.39-1.90]) and over the lifespan (IRR 1.55, [1.33-1.81]). Among CHEU, significant risk factors for hospitalization on univariate regression analysis included birth year before 2005, prematurity, small for gestational age (SGA), detectable maternal viral load (dVL) at delivery, and maternal hepatitis C co-infection. In the adjusted analysis, small for gestational age and dVL remained significant risk factors. CONCLUSIONS: CHEU had a higher rate of hospitalization than CHUU controls across their lifespan. Significant risk factors included SGA and detectable maternal dVL, suggesting a need enhanced pediatric care for these children.

From Pancytopenia to Hyperleukocytosis, an Unexpected Presentation of Immune Reconstitution Inflammatory Syndrome in an Infant with Methylmalonic Acidemia.

A 2.5-month-old girl admitted for failure to thrive and severe pancytopenia was diagnosed with methylmalonic acidemia (MMA) secondary to transcobalamin II deficiency, an inborn error of vitamin B12 metabolism. Opportunistic Cytomegalovirus and Pneumocystis jirovecii pneumonia led to severe acute respiratory distress syndrome (ARDS) and immune reconstitution inflammatory syndrome (IRIS) after treatment initiation with vitamin B12 supplementation. In children with interstitial pneumonia-related ARDS, normal lymphocyte count should not delay invasive procedures required to document opportunistic infections. MMA can be associated with underlying lymphocyte dysfunction and vitamin B12 supplementation can fully reverse the associated immunodeficiency. IRIS may appear in highly treatment-responsive forms of pancytopenia in children and prompt treatment of dysregulated inflammation with high-dose corticosteroids should be initiated.

Lower Neutrophil Count Without Clinical Consequence Among Children of African Ancestry Living With HIV in Canada.

OBJECTIVE: To investigate the association between African ancestry and neutrophil counts among children living with HIV (CLWH). We also examined whether medications, clinical conditions, hospitalization, or HIV virologic control were associated with low neutrophil counts or African ancestry. DESIGN: We conducted a secondary analysis of the Early Pediatric Initiation Canada Child Cure Cohort (EPIC4) Study, a multicenter prospective cohort study of CLWH across 8 Canadian pediatric HIV care centers. METHODS: We classified CLWH according to African ancestry, defined as "African," "Caribbean," or "Black" maternal race. Longitudinal laboratory data (white blood cells, neutrophils, lymphocytes, viral load, and CD4 count) and clinical data (hospitalizations, AIDS-defining conditions, and treatments) were abstracted from medical records. RESULTS: Among 217 CLWH (median age 14, 55% female), 145 were of African ancestry and 72 were of non-African ancestry. African ancestry was associated with lower neutrophil counts, white blood cell counts, and neutrophil-lymphocyte ratios. Neutrophil count <1.5 × 109/L was detected in 60% of CLWH of African ancestry, compared with 31% of CLWH of non-African ancestry (P < 0.0001), representing a 2.0-fold higher relative frequency (95% CI: 1.4-2.9). Neutrophil count was on average 0.74 × 109/L (95% CI: 0.45 to 1.0) lower in CLWH of African ancestry (P < 0.0001). Neither neutrophil count<1.5 × 109/L nor African ancestry was associated with medications, hospitalizations, AIDS-defining conditions, or markers of virologic control (viral load, sustained viral suppression, and lifetime nadir CD4). CONCLUSIONS: In CLWH, African ancestry is associated with lower neutrophil counts, without clinical consequences. A flexible evaluation of neutrophil counts in CLWH of African ancestry may avoid unnecessary interventions.

Chronic and Latent Viral Infections and Leukocyte Telomere Length across the Lifespan of Female and Male Individuals Living with or without HIV.

BACKGROUND: Chronic/latent viral infections may accelerate immunological aging, particularly among people living with HIV (PLWH). We characterized chronic/latent virus infections across their lifespan and investigated their associations with leukocyte telomere length (LTL). METHODS: Participants enrolled in the CARMA cohort study were randomly selected to include n = 15 for each decade of age between 0 and >60 y, for each sex, and each HIV status. Cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), herpes simplex virus 1 (HSV-1), and HSV-2 infection were determined serologically; HIV, hepatitis C (HCV), and hepatitis B (HBV) were self-reported. LTLs were measured using monochrome multiplex qPCR. Associations between the number of viruses, LTL, and sociodemographic factors were assessed using ordinal logistic and linear regression modeling. RESULTS: The study included 187 PLWH (105 female/82 male) and 190 HIV-negative participants (105 female/84 male), ranging in age from 0.7 to 76.1 years. Living with HIV, being older, and being female were associated with harbouring a greater number of chronic/latent non-HIV viruses. Having more infections was in turn bivariately associated with a shorter LTL. In multivariable analyses, older age, living with HIV, and the female sex remained independently associated with having more infections, while having 3-4 viruses (vs. 0-2) was associated with a shorter LTL. CONCLUSIONS: Our results suggest that persistent viral infections are more prevalent in PLWH and females, and that these may contribute to immunological aging. Whether this is associated with comorbidities later in life remains an important question.

The Effect of Age and Comorbidities: Children vs. Adults in Their Response to SARS-CoV-2 Infection.

While children have experienced less severe coronavirus disease (COVID-19) after SARS-CoV-2 infection than adults, the cause of this remains unclear. The objective of this study was to describe the humoral immune response to COVID-19 in child vs. adult household contacts, and to identify predictors of the response over time. In this prospective cohort study, children with a positive SARS-CoV-2 polymerase chain reaction (PCR) test (index case) were recruited along with their adult household contacts. Serum IgG antibodies against SARS-CoV-2 S1/S2 spike proteins were compared between children and adults at 6 and 12 months after infection. A total of 91 participants (37 adults and 54 children) from 36 families were enrolled. Overall, 78 (85.7%) participants were seropositive for anti-S1/S2 IgG antibody at 6 months following infection; this was higher in children than in adults (92.6% vs. 75.7%) (p = 0.05). Significant predictors of a lack of SARS-CoV-2 seropositivity were age ≥ 25 vs. < 12 years (odds ratio [OR] = 0.23, p = 0.04), presence of comorbidities (vs. none, adjusted OR = 0.23, p = 0.03), and immunosuppression (vs. immunocompetent, adjusted OR = 0.17, p = 0.02).

Factors associated with HIV viral load control in the early postpartum period - a Canadian prospective cohort study.

Despite success in managing HIV during pregnancy, challenges remain around sustained adherence with antiretroviral therapy (ART), and the suboptimal viral load (VL) suppression during the postpartum period. The objective of this study was to compare VL levels at delivery and during the postpartum period and assess factors associated with lack of viral suppression during the postpartum period in Canada. We combined data from two Canadian prospective cohorts, which included 286 HIV-positive women (352 pregnancies) who delivered between 2012 and 2020. Delivery VL, postpartum VL, and potential factors associated with an undetectable VL (<50 copies/mL), 2-18 weeks after delivery were assessed. To account for the correlation between multiple pregnancies from the same woman, generalized estimating equations were used to assess bivariate associations. Ninety-nine per cent of pregnant women were on ART during pregnancy compared to 93% during the postpartum period. Of those with available VL results (n = 214 pregnancies), 94% of women achieved an undetectable VL at delivery compared to 87% during the postpartum period. The postpartum period is a challenging time for ART use and VL control. Qualitative studies are needed to better understand these challenges and guide us in designing adequate interventions.

Risk of SARS-CoV-2 Reinfection in Children Within the 12 Months Following Mild COVID-19: Insights From a Survey Study.

Understanding the correlation between immune response and protection from COVID-19 will play a pivotal role in predicting the effectiveness of vaccines in children. We studied SARS-CoV-2 reinfection risk in children 12 months post-mild COVID-19. Children under 5 years old exhibited lower reinfection risk than older infected or vaccinated siblings during 12 months postimmunization.

Variations in CD4 counts during pregnancy in women living with HIV.

OBJECTIVE: Our objective was to determine the frequency at which CD4 counts drop below 200 cells/mm3 during pregnancy in women living with HIV and to identify factors associated with this. METHODS: Data from 2005 to 2020 from two prospective Canadian cohorts of pregnant women living with HIV were extracted. As per national guidelines, women received antiretroviral therapy and CD4 counts were monitored once per trimester and at delivery. RESULTS: Among 775 included cases, 72 (9.3%) had CD4 counts <200 cells/mm3 at the first pregnancy visit. Of the 703 remaining pregnancies with CD4 counts ≥200 cells/mm3 at the initial visit, 20 (2.8%) were associated with a drop to <200 cells/mm3 . In univariate analysis, factors associated with this drop were coinfection with hepatitis B virus or hepatitis C virus (odds ratio [OR] 4.0, 95% confidence interval [CI] 1.52-10.50), lower first visit CD4 counts (OR 0.165, 95% CI 0.08-0.34), and baseline haemoglobin levels <11 g/dL (OR 2.89, 95% CI 1.04-8.00). In multivariable analysis, only CD4 count at first visit remained independently associated with this drop. A cut-off CD4 count ≤450 cells/mm3 at the first pregnancy visit had a sensitivity of 100% to detect cases of CD4 drop to <200 cells/mm3 . CONCLUSION: A drop of CD4 count to <200 cells/mm3 is uncommon during pregnancy in women living with HIV. Our results suggest that CD4 monitoring only once in pregnancy would be safe in women whose CD4 count is >450 cells/mm3 at the first pregnancy visit.

Gen Z and HIV-Strategies for Optimizing the Care of the Next Generation of Adolescents Living with HIV.

The management of adolescents living with HIV represents a particular challenge in the global response to HIV. The challenges specific to this age group include difficulties engaging and maintaining them in care, challenges with transition to adult care, and limited therapeutic options for treatment-experienced patients, all of which have been jeopardized by the COVID-19 pandemic. This paper summarizes some of the challenges in managing adolescents living with HIV, as well as some of the most recent and innovative therapeutic approaches in this population.

Clinical features of COVID-19 in Italian outpatient children and adolescents during Parental, Delta, and Omicron waves: a prospective, observational, cohort study.

Introduction: COVID-19 features changed with the Omicron variant of SARS-CoV-2 in adults. This study aims to describe COVID-19 symptoms in children and adolescents during the Parental, Delta, and Omicron eras. Methods: A single-centre, prospective observational study was conducted on individuals aged 0-20 years attending the University Hospital of Padua (Italy) from April 2020 to December 2022. COVID-19 cases were defined by positive SARS-CoV-2 molecular detection and/or serology; patient/family symptoms and virological positivity were considered to determine the infection onset. Variables were summarized and compared using appropriate tests of descriptive statistics. Results: A total of 509 cases [46% female, median age eight years (IQR: 4-12)] were studied. Three-hundred-eighty-seven (76%), 52 (10%), and 70 (14%) subjects experienced COVID-19 during the Parental, Delta, and Omicron waves, respectively. All subjects developed an asymptomatic/mild COVID-19. Overall, the most frequent symptoms were fever (47%) and rhinitis (21%), which showed a significant increasing incidence from the Parental to Omicron waves (p < 0.001). Conversely, diarrhea was most common during the pre-Omicron eras (p = 0.03). Stratifying symptoms according to the age group, fever, rhinitis, and skin rashes were observed more frequently among infants/toddlers; conversely, fatigue was more common in children older than five years. The duration of symptoms was similar across different SARS-CoV-2 variants of concern (VOCs); conversely, the number of symptoms varied according to the age group (p < 0.0001). Discussion: This study showed differences in COVID-19 clinical presentation among infants, children, and adolescents and confirmed Omicron infection is more likely to be associated with upper respiratory symptoms. However, further population-based studies are needed to support these findings. In addition, active surveillance will play a crucial role in assessing the disease severity of future VOCs.

Identifying Clinical Criteria for an Expanded Targeted Approach to Screening for Congenital Cytomegalovirus Infection-A Retrospective Study.

Targeted screening for congenital CMV infection (cCMV), which entails CMV testing of infants who fail newborn hearing screening (NBHS), has become common practice. However, this strategy misses nearly all infected infants with normal hearing at birth who are nonetheless at high risk of subsequent hearing loss and would benefit from timely cCMV diagnosis. The objective of this study was to identify expanded criteria predictive of cCMV to increase the scope and utility of targeted newborn CMV screening. In this retrospective study, 465 newborns were tested for cCMV at a single tertiary care center with a targeted screening program between 2014 and 2018. Twenty-two infants were diagnosed with cCMV, representing 0.2% of the 12,189 births over this period and 4.7% of the infants tested. The highest prevalence of cCMV infection was among infants tested because of primary maternal CMV infection (8/42, 19%), followed by failed initial NBHS (10/88, 11.4%), maternal HIV infection (3/137, 2.2%), and clinical suspicion alone (5/232, 2.2%). The symptoms with the highest prevalence of infection among all infants tested included an enlarged liver and/or spleen (33.3%) (3/9), followed by petechiae (33.3%), microcephaly (9.4%), direct hyperbilirubinemia (7.7%), thrombocytopenia (6%), and growth impairment (4.3%). In addition to CMV screening of newborns who fail the NBHS, these data suggest that certain clinical signs of cCMV-in particular: thrombocytopenia, growth impairment, and HIV exposure in pregnancy-should be additional criteria for expanded targeted newborn CMV screening, where universal screening is not yet the standard of care.

Placenta analysis of Hofbauer cell profile according to the class of antiretroviral therapy used during pregnancy in people living with HIV.

INTRODUCTION: The use of antiretroviral therapy drastically reduces vertical transmission of Human Immunodeficiency Virus. However, recent studies demonstrate associations between ART use during pregnancy and placental inflammation, particularly within protease inhibitor (PI)-based regimens. We sought to characterize placental macrophages, namely Hofbauer cells, according to the class of ART used during pregnancy. METHODS: Using immunofluorescence and immunohistochemistry, placentas from 79 pregnant people living with HIV (PPLWH) and 29 HIV-uninfected people were analyzed to quantify the numbers and frequencies of leukocytes (CD45+) and Hofbauer cells (CD68+ and/or CD163+). PPLWH were stratified into three groups based on class of ART: non-nucleoside reverse transcriptase inhibitor (NNRTI)-based, integrase strand-transfer inhibitor (INSTI)-based, and PI-based regimens. RESULTS: Placentas of PPLWH contained significantly more leukocytes and Hofbauer cells than controls. Multivariable analyses revealed that this increase in immune cells was associated with a predominantly CD163+ profile in all ART subgroups compared to the HIV-negative group. This was characterized by an increase in total CD163+ cells in the PI and INSTI subgroups, and a higher frequency of CD163+ cells and CD163+/CD68+ ratio in the NNRTI and PI subgroups. DISCUSSION: Placentas of PPLWH treated with any ART regimen during their entire pregnancy displayed a selection for CD163+ cells compared to the HIV-negative group, regardless of class of ART, suggesting that class of ART does not intrinsically affect selection of CD163+ and CD68+ Hofbauer cells. Further investigations into the role of Hofbauer cells in ART-associated placental inflammation are warranted to identify the mechanisms behind their potential involvement in maternal-fetal tolerance maintenance.

Paediatric inflammatory multisystem syndrome in Canada: population-based surveillance and role of SARS-CoV-2 linkage.

BACKGROUND: Paediatric inflammatory multisystem syndrome (PIMS) is a rare condition temporally associated with SARS-CoV-2 infection. Using national surveillance data, we compare presenting features and outcomes among children hospitalized with PIMS by SARS-CoV-2 linkage, and identify risk factors for intensive care (ICU). METHODS: Cases were reported to the Canadian Paediatric Surveillance Program by a network of >2800 pediatricians between March 2020 and May 2021. Patients with positive versus negative SARS-CoV-2 linkages were compared, with positive linkage defined as any positive molecular or serologic test or close contact with confirmed COVID-19. ICU risk factors were identified with multivariable modified Poisson regression. RESULTS: We identified 406 children hospitalized with PIMS, including 49.8% with positive SARS-CoV-2 linkages, 26.1% with negative linkages, and 24.1% with unknown linkages. The median age was 5.4 years (IQR 2.5-9.8), 60% were male, and 83% had no comorbidities. Compared to cases with negative linkages, children with positive linkages experienced more cardiac involvement (58.8% vs. 37.4%; p < 0.001), gastrointestinal symptoms (88.6% vs. 63.2%; p < 0.001), and shock (60.9% vs. 16.0%; p < 0.001). Children aged ≥6 years and those with positive linkages were more likely to require ICU. CONCLUSIONS: Although rare, 30% of PIMS hospitalizations required ICU or respiratory/hemodynamic support, particularly those with positive SARS-CoV-2 linkages. IMPACT: We describe 406 children hospitalized with paediatric inflammatory multisystem syndrome (PIMS) using nationwide surveillance data, the largest study of PIMS in Canada to date. Our surveillance case definition of PIMS did not require a history of SARS-CoV-2 exposure, and we therefore describe associations of SARS-CoV-2 linkages on clinical features and outcomes of children with PIMS. Children with positive SARS-CoV-2 linkages were older, had more gastrointestinal and cardiac involvement, and hyperinflammatory laboratory picture. Although PIMS is rare, one-third required admission to intensive care, with the greatest risk amongst those aged ≥6 years and those with a SARS-CoV-2 linkage.

Canadian Pediatric & Perinatal HIV/AIDS Research Group consensus recommendations for infant feeding in the HIV context.

Background: Providing comprehensive infant feeding guidance to families affected by HIV is complex and requires a multidisciplinary approach. While exclusive formula feeding remains the preferred recommendation for infants born to women living with HIV (WLWH) in high-income countries, a more nuanced approach that may include the option of breastfeeding under certain circumstances is emerging in many resource-rich countries. Methods: The Canadian Pediatric & Perinatal HIV/AIDS Research Group (CPARG) hosted a Canadian Institute of Health Research-funded meeting in 2016 to develop consensus among multidisciplinary providers around counselling and recommendations for infant feeding. After presentations by adult and paediatric health care providers, basic scientists, and community-based researchers, a subgroup drafted summary evidence-informed recommendations. Along with revisions among CPARG members, a community review was performed by a convenience sample of WLWH who had given birth in the past 5 years from Ontario and Quebec. A legal review was also conducted to ensure understanding of the criminalization potential and concern of HIV transmission and exposure. Results: The Canadian consensus guidelines continue to support formula feeding as the preferred method of infant feeding as it eliminates any residual risk of postnatal vertical transmission. Formula should be made available for all infants born to mothers living with HIV for their first year of life. A comprehensive approach to counselling WLWH is outlined to assist providers to effectively counsel on current evidence to ensure WLWH are fully informed in their decision making. For women meeting criteria to and elect to breastfeed, frequent maternal virologic monitoring and follow-up is required of both mother and infant. Antiretroviral prophylaxis and monitoring are recommended for breastfed infants. The community review highlighted the importance of other supports and counselling needed for implementing effective formula feeding, aside from access to formula. The legal review provided clarifying language around child protection services involvement and the need to provide referral to legal resources or information upon request. Surveillance systems to monitor for cases of breastmilk transmission should be in place to improve gaps in care and develop further knowledge in this area. Conclusion: The Canadian infant feeding consensus guideline is designed to inform and enable better care for WLWH and their babies. Ongoing evaluation of these guidelines as new evidence emerges will be important.

Historique: La transmission de conseils détaillés sur l'alimentation du nourrisson aux familles touchée par le VIH est complexe et exige une approche multidisciplinaire. Il est recommandé de recourir exclusivement aux préparations commerciales chez les nourrissons de mères vivant avec le VIH (MVIH) dans les pays à revenu élevé, mais une approche plus nuancée, qui peut inclure l'allaitement dans certaines situations, émerge dans de nombreux pays riches en ressources. Méthodologie: Le Groupe canadien de recherche pédiatrique et périnatale sur le VIH/sida (CPARG) a tenu un congrès financé par Les Instituts de recherche en santé du Canada en 2016 pour parvenir à un consensus de la part des professionnels multidisciplinaires sur le counseling et les recommandations à l'égard de l'alimentation du nourrisson. Après les présentations de professionnels de la santé pédiatrique, de chercheurs fondamentaux et de chercheurs communautaires, un sous-groupe a rédigé une synthèse des recommandations reposant sur des données probantes. En plus des révisions proposées par les membres de la CPARG, un échantillon de commodité de MVIH qui avaient accouché dans les cinq années précédentes en Ontario et au Québec a procédé à un examen communautaire. Une révision juridique a également permis de bien comprendre le potentiel de criminalisation et les inquiétudes quant à la transmission du VIH et à l'exposition à ce virus. Résultats: Les lignes directrices consensuelles canadiennes continuent de préconiser l'utilisation des préparations commerciales pour l'alimentation des nourrissons, car elles éliminent tout risque résiduel de transmission verticale après la naissance. Ces préparations doivent être mises à la disposition de tous les nourrissons nés de MVIH jusqu'à l'âge d'un an. Une approche détaillée du counseling auprès des MVIH est présentée pour aider les professionnels à leur donner des conseils efficaces sur les données probantes à jour, afin qu'elles puissent prendre une décision pleinement éclairée. Chez les femmes qui respectent les critères et qui choisissent d'allaiter, la surveillance virologique fréquente de la mère et un suivi de la mère et du nourrisson s'imposent. La prophylaxie antirétrovirale et la surveillance des nourrissons allaités sont recommandées. La révision communautaire a fait ressortir l'importance d'autres mesures de soutien et de counseling pour mettre en place une alimentation efficace à l'aide des préparations commerciales, en plus de l'accès à ces préparations. L'analyse juridique a permis de préciser les énoncés entourant la participation des services de protection de l'enfance et la nécessité de diriger les familles vers des ressources ou de l'information juridiques, sur demande. Des systèmes de surveillance visant à répertorier les cas de transmission par le lait maternel devraient être en place pour corriger les lacunes en matière de soins et accroître les connaissances dans ce domaine. Conclusion: Les lignes directrices consensuelles canadiennes sur l'alimentation des nourrissons sont conçues pour éclairer les soins aux MVIH et à leurs nourrissons et pour les améliorer. Il sera important d'assurer l'évaluation continue de ces lignes directrices à mesure que de nouvelles données probantes seront découvertes.

Breastfeeding Among People With Human Immunodeficiency Virus in North America: A Multisite Study.

BACKGROUND: In North American countries, national guidelines have strongly recommended formula over breastmilk for people with human immunodeficiency virus (HIV) because of concern for HIV transmission. However, data from resource-limited settings suggest the risk is <1% among virally suppressed people. Information regarding breastfeeding experience in high-resource settings is lacking. METHODS: A retrospective multisite study was performed for individuals with HIV who breastfed during 2014-2022 in the United States (8 sites) and Canada (3 sites). Descriptive statistics were used for data analysis. RESULTS: Among the 72 cases reported, most had been diagnosed with HIV and were on antiretroviral therapy prior to the index pregnancy and had undetectable viral loads at delivery. Most commonly reported reasons for choosing to breastfeed were health benefits, community expectations, and parent-child bonding. Median duration of breastfeeding was 24 weeks (range, 1 day to 72 weeks). Regimens for infant prophylaxis and protocols for testing of infants and birthing parents varied widely among institutions. No neonatal transmissions occurred among the 94% of infants for whom results were available ≥6 weeks after weaning. CONCLUSIONS: This study describes the largest cohort to date of people with HIV who breastfed in North America. Findings demonstrate high variability among institutions in policies, infant prophylaxis, and infant and parental testing practices. The study describes challenges in weighing the potential risks of transmission with personal and community factors. Finally, this study highlights the relatively small numbers of patients with HIV who chose to breastfeed at any 1 location, and the need for further multisite studies to identify best care practices.

Type and timing of antiretroviral therapy during pregnancy: Impact on risk of preterm delivery and small-for-gestational age births in Canada, a retrospective cohort study.

OBJECTIVE: To evaluate the impact of type and timing of antiretroviral therapy (ART) on the risk of preterm delivery (PTD) and small-for-gestational age (SGA) birth among pregnant women and people living with HIV in Canada. METHODS: Data for this retrospective cohort study were analyzed from the Canadian Perinatal HIV Surveillance Program from 1990 to 2020. The association between ART and risk of PTD (<37 weeks) and SGA birth (<10th percentile) was explored using mixed effects logistic regression and time-dependent Cox proportional hazards models. RESULTS: Overall, there were 14.9% (654 of 4379) PTD and 18.5% (732 of 3947) SGA cases. A higher risk of PTD was observed with nonnucleoside reverse transcriptase inhibitor-(adjusted hazard ratio [aHR], 1.73; P = 0.019) and boosted protease inhibitor- (aHR, 186; P = 0.007) based regimens compared with integrase strand transfer inhibitor (INSTI)-based regimens. ART initiation prior to conception was associated with a lower risk of SGA birth compared with ART initiation after conception at 1 to 14 weeks (adjusted odds ratio [aOR], 0.69; P = 0.024) and > 14 weeks (aOR, 0.70; P = 0.005). CONCLUSION: INSTI-based ART regimens were associated with lower risk of PTD compared with other regimens, and ART initiation before conception was associated with a lower risk of SGA birth. These findings, with overall safety data, should be considered when providing pregnancy counseling to people living with HIV.

Prescribing patterns of antiretroviral treatments during pregnancy for women living with HIV in Canada 2004-2020: A surveillance study.

BACKGROUND: While treatment guidelines for HIV in adults have evolved rapidly with the advent of new antiretroviral (ARV) treatment, those for the prevention of vertical HIV transmission in pregnancy have evolved more slowly due to safety and efficacy concerns. Here we describe Canadian prescribing patterns for ARV treatments during pregnancy and compare them to perinatal HIV prescribing guidelines of the United States Department of Health and Human Services (HHS), that are commonly used in Canada and include recommendations for newly commercialized therapies. METHODS: The Canadian Perinatal HIV Surveillance Program (CPHSP) captures annual medical data on mothers living with HIV and their infants from 23 sites across Canada. Women from this cohort who received an ARV treatment during pregnancy and who gave birth between 2004 and 2020 were included in the study. ARV treatments were designated as 'preferred/alternative' as per HHS HIV perinatal guidelines, or 'other than preferred/alternative'. RESULTS: We identified 3673 pregnancies from 2720 women. The proportion of women that conceived while on ARV treatment increased from 29% in 2003 to 90% in 2020. Other than preferred/alternative ARV treatments were received in 1112 (30%) of pregnancies and this was significantly associated with having initiated ARV treatment before conception. CONCLUSION: In Canada during the study period, a high number of women were prescribed an other than preferred/alternative ARV treatment during pregnancy. Further optimization of ARV treatment in women of childbearing age living with HIV is warranted.

Relationship between raltegravir trough plasma concentration and virologic response and the impact of therapeutic drug monitoring during pregnancy.

BACKGROUND: Limited data is available on raltegravir (RAL) pharmacokinetics during pregnancy and the value of therapeutic drug monitoring (TDM) in pregnancy is unknown. This study aims to describe RAL trough plasma concentrations (Ctrough) during pregnancy and review the impact of RAL TDM on outcomes. METHODS: Women from the prospective mother-infant HIV cohort of Mother and Children's Infectious Diseases Center who received RAL during their pregnancy between 2011-2020 were included. TDM reports were reviewed and Ctrough values estimated when possible, using historical RAL half-lives. RESULTS: We included 76 pregnant women of which 47 underwent TDM. We observed a significant association between virological response and Ctrough (p-value .034) with an increase of 0.1 mg/L corresponding to a 2.96 reduction in the risk of having a detectable viral load. The results indicated that in pregnant women a RAL Ctrough threshold of 0.04 mg/L has a higher specificity (75%) as compared to our current Ctrough target value of 0.02 mg/L (25%) and an acceptable sensitivity (77%). No significant differences were observed between Ctrough at each trimester. When comparing pregnancies with and without TDM, no statistically significant differences were observed in the virologic response during pregnancy and at delivery, or with the need for triple antiretroviral prophylaxis in newborns. CONCLUSIONS: An association between RAL Ctrough and viral load was observed and achieving a RAL Ctrough of 0.04 mg/L or greater is a predictor of virologic response in pregnant women. The impact of TDM in pregnancy, however, could not be demonstrated.

Resource use and disease severity of children hospitalized for COVID-19 versus multisystem inflammatory syndrome in children (MIS-C) in Canada.

Background: Direct comparisons of paediatric hospitalizations for acute coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C) can inform health system planning. We describe the absolute and relative hospital burden of acute paediatric COVID-19 and MIS-C in Canada. Methods: This national prospective study was conducted via the Canadian Paediatric Surveillance Program from March 2020-May 2021. Children younger than 18 years old and hospitalized for acute COVID-19 or MIS-C were included in the analysis. Outcomes included supplemental oxygen (low-flow oxygen or high-flow nasal cannula), ventilation (non-invasive or conventional mechanical), vasopressors, paediatric intensive care unit (PICU) admission, or death. Adjusted risk differences (aRD) and 95% confidence intervals (CI) were calculated to identify factors associated with each diagnosis. Results: Overall, we identified 330 children hospitalized for acute COVID-19 (including five deaths) and 208 hospitalized for MIS-C (including zero deaths); PICU admission was required for 49.5% of MIS-C hospitalizations versus 18.2% of acute COVID-19 hospitalizations (aRD 20.3; 95% CI, 9.9-30.8). Resource use differed by age, with children younger than one year hospitalized more often for acute COVID-19 (aRD 43.4% versus MIS-C; 95% CI, 37.7-49.1) and more children 5-11 years hospitalized for MIS-C (aRD 38.9% vs. acute COVID-19; 95% CI, 31.0-46.9). Conclusion: While there were more hospitalizations and deaths from acute paediatric COVID-19, MIS-C cases were more severe, requiring more intensive care and vasopressor support. Our findings suggest that both acute COVID-19 and MIS-C should be considered when assessing the overall burden of severe acute respiratory syndrome coronavirus 2 in hospitalized children.

Chitinase-3-like Protein 1 Is Associated with Poor Virologic Control and Immune Activation in Children Living with HIV.

Perinatally infected children living with HIV (CLWH) face lifelong infection and associated inflammatory injury. Chitinase-like 3 protein-1 (CHI3L1) is expressed by activated neutrophils and may be a clinically informative marker of systemic inflammation in CLWH. We conducted a multi-centre, cross-sectional study of CLWH, enrolled in the Early Pediatric Initiation Canadian Child Cure Cohort Study (EPIC4). Plasma levels of CHI3L1, pro-inflammatory cytokines, and markers of microbial translocation were measured by enzyme-linked immunosorbent assays. Longitudinal clinical characteristics (viral load, neutrophil count, CD4+ and CD8+ T-lymphocyte counts, and antiretroviral (ARV) regimen) were abstracted from patient medical records. One-hundred-and-five (105) CLWH (median age 13 years, 62% female) were included in the study. Seventy-seven (81%) had viral suppression on combination antiviral therapy (cART). The median CHI3L1 level was 25 µg/L (IQR 19-39). CHI3L1 was directly correlated with neutrophil count (ρ = 0.22, p = 0.023) and inversely correlated with CD4/CD8 lymphocyte ratio (ρ = -0.35, p = 0.00040). Children with detectable viral load had higher levels of CHI3L1 (40 µg/L (interquartile range, IQR 33-44) versus 24 µg/L (IQR 19-35), p = 0.0047). CHI3L1 levels were also correlated with markers of microbial translocation soluble CD14 (ρ = 0.26, p = 0.010) and lipopolysaccharide-binding protein (ρ = 0.23, p = 0.023). We did not detect differences in CHI3L1 between different cART regimens. High levels of neutrophil activation marker CHI3L1 are associated with poor virologic control, immune dysregulation, and microbial translocation in CLWH on cART.