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.

HIV pre-exposure prophylaxis: It is time to consider harm reduction care for adolescents in Canada.

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.

Biomarkers of Growth Faltering and Neurodevelopmental Delay in Children who are HIV-Exposed but Uninfected: A Systematic Review.

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-1ß, -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.

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.

Practices, support and stigma related to infant feeding and postpartum engagement in care among women living with HIV in Canada.

Background: Breastfeeding is not recommended for women living with HIV (WLWH) in Canada. We described the prevalence of breastfeeding and explored experiences of care, support, and stigma related to infant feeding. Setting: Quebec, Ontario, and British Columbia (Canada). Methods: Data were obtained from the HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS) surveys, conducted between 2013 and 2018. Results: Breastfeeding was reported by 73.5% of the 786 women who delivered before HIV diagnosis and 7.3% of the 289 women who delivered after HIV diagnosis. Among them, earlier year of delivery, delivery outside of Canada, and African, Caribbean, Black ethnicity were independently associated with increased odds of breastfeeding. Among WLWH who had a live birth during the last year, 77% (40/52) felt that they had received support regarding infant feeding practices, and 77% (23/30) were concerned that not breastfeeding could lead to them being identified as WLWH. Among 71 women within one year postpartum at any one of the study waves, 89% reported having an undetectable viral load. Conclusion: Breastfeeding experiences were common among WLWH, most often prior to HIV diagnosis. Fear of unintentional HIV status disclosure when not breastfeeding and challenges to maintain an undetectable HIV viral load are important issues to address during postpartum care.

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.

Evolution of prevention of vertical HIV transmission in Uganda: 2008-2017.

OBJECTIVES: 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. METHODS: This is is a retrospective observational study of infants attending early infant diagnosis clinics at two Ugandan hospitals. RESULTS: 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. CONCLUSIONS: From 2009 to 2017, outcomes improved among HIV-exposed infants in Uganda. LTFU remains a barrier to optimal care.

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.

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.

A two-day workshop reviewing Canadian provincial and national HIV care cascade indicators, reporting, challenges, and recommendations.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

HISTORIQUE: 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. MÉTHODOLOGIE: 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. RÉSULTATS: 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. CONCLUSION: 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.

Evaluation of TB elimination strategies in Canadian Inuit populations: Nunavut as a case study.

Tuberculosis (TB) continues to disproportionately affect Inuit populations in Canada with some communities having over 300 times higher rate of active TB than Canadian-born, non-Indigenous people. Inuit Tuberculosis Elimination Framework has set the goal of reducing active TB incidence by at least 50% by 2025, aiming to eliminate it by 2030. Whether these goals are achievable with available resources and treatment regimens currently in practice has not been evaluated. We developed an agent-based model of TB transmission to evaluate timelines and milestones attainable in Nunavut, Canada by including case findings, contact-tracing and testing, treatment of latent TB infection (LTBI), and the government investment on housing infrastructure to reduce the average household size. The model was calibrated to ten years of TB incidence data, and simulated for 20 years to project program outcomes. We found that, under a range of plausible scenarios with tracing and testing of 25%-100% of frequent contacts of detected active cases, the goal of 50% reduction in annual incidence by 2025 is not achievable. If active TB cases are identified rapidly within one week of becoming symptomatic, then the annual incidence would reduce below 100 per 100,000 population, with 50% reduction being met between 2025 and 2030. Eliminating TB from Inuit populations would require high rates of contact-tracing and would extend beyond 2030. The findings indicate that time-to-identification of active TB is a critical factor determining program effectiveness, suggesting that investment in resources for rapid case detection is fundamental to controlling TB.

Factors associated with contraceptive use among women living with HIV in Canada: a controlled, cross-sectional study.

BACKGROUND: Multiple contraindications to combined hormonal contraceptives (CHC) use exist. The impact of these factors on contraceptive choice, particularly among women living with HIV (WLWH), is not well understood. We measured and compared the prevalence of contraceptive use and contraindications among WLWH and women not living with HIV (controls). METHODS: We examined cross-sectional survey and medical chart data from 83 WLWH and 62 controls, aged 16-49 and sexually active, from 2013-2017. We compared the age-adjusted prevalence and types of contraceptives used in the last month and the proportion of women with CHC contraindications, including drug interactions, medical comorbidities, and smoking at ≥ 35 years old. All WLWH received care at an interdisciplinary, women-centred HIV clinic. RESULTS: Compared to controls, WLWH were older (median [IQR)] 39 [34-43] vs 31 [23-41] years; p = 0.003), had less post-secondary education (37% vs 73%; p < 0.001), and more often had household income < $15,000/year (49% vs 30%; p = 0.006). WLWH trended to higher contraceptive prevalence than controls (80% vs 63%; p = 0.06 adjusted for age). Overall hormonal contraceptive use was similar. However, despite controlling for age, WLWH used CHC less (4% vs 18%; p = 0.006) than controls, and had more frequently undergone tubal ligation (12% vs 2%; p = 0.03). WLWH also experienced more CHC contraindications (54% vs 13%; p = 0.0001), including smoking at ≥ 35 years old (30% vs 6%; p = 0.0003) or a CHC-related drug interaction (all antiretroviral related) (25% vs 0%; p = 0.0001). CONCLUSIONS: WLWH attending our interdisciplinary clinic used hormonal contraception at similar rates as controls, though with different types. Differences may reflect different distributions of CHC contraindications. CHC contraindications present barriers to accessing the full range of contraceptive choices for WLWH. Guidelines and education for care providers and WLWH regarding contraceptive choices and drug interactions are needed, especially when care is provided without the benefit of an interdisciplinary women-centered healthcare team.

BACKGROUND: There are many reasons why individuals cannot use combined hormonal contraceptives (CHC). The impact of these reasons on contraceptive choice for women living with HIV (WLWH) are poorly understood. We measured and compared the prevalence of contraceptive choice and factors that may preclude their use in WLWH. METHODS: We examined survey and medical chart data from 83 WLWH and 62 controls (women not living with HIV), aged 16­49 and sexually active, from 2013 to 2017. We compared the prevalence and types of contraceptives used in the last month and the proportion of women with factors that would not allow the use of CHC, including drug interactions, medical conditions, and smoking at ≥ 35 years old. All WLWH received care at a women-centred HIV clinic. RESULTS: Compared to controls, WLWH were older, had less post-secondary education, and more often had household income < $15,000/year. WLWH were more likely to use contraception than controls. Overall hormonal contraceptive use was similar. However, even when accounting for age, WLWH used CHC less than controls, and had more frequently undergone tubal ligation. WLWH also had more reasons that would preclude the use of CHC contraindications including smoking at ≥ 35 years old or a CHC-related drug interaction. CONCLUSIONS: WLWH attending our interdisciplinary clinic used combined hormonal contraception at similar rates as controls, though with different types. Differences may reflect the fact that WLWH more often have factors that do not allow the safe use of CHC. Guidelines and education for care providers and WLWH regarding contraceptive choices and drug interactions are needed.

Is 'conflict of interest' a Misnomer? Managing interests in immunization research and evaluation.

Potential conflicts of interest in vaccine research can lead to negative consequences that undermine public trust and thereby put communities at risk. However, collaborations that may give rise to potential conflicts between interests can also greatly facilitate appropriate, scientifically robust, and timely vaccine development, implementation, and evaluation. At present, policies regarding the management of potential conflicts between interests are not ideal. To optimally manage interests in vaccine research, we recommend acknowledging all forms of interests and treating them all as relevant, developing appropriate collaborations, referring to all "conflicts of interest" simply as "interests" or "declarations," and promoting transparency through developing consistent reporting mechanisms.

British Columbia CARMA-CHIWOS Collaboration (BCC3): protocol for a community-collaborative cohort study examining healthy ageing with and for women living with HIV.

INTRODUCTION: Women living with HIV (WLWH) experience accelerated ageing and an increased risk of age-associated diseases earlier in life, compared with women without HIV. This is likely due to a combination of viral factors, gender differences, hormonal imbalance and psychosocial and structural conditions. This interdisciplinary cohort study aims to understand how biological, clinical and sociostructural determinants of health interact to modulate healthy ageing in WLWH. METHODS AND ANALYSIS: The British Columbia Children and Women: AntiRetroviral therapy and Markers of Aging-Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CARMA-CHIWOS) Collaboration (BCC3) study will enrol WLWH (n=350) and sociodemographically matched HIV-negative women (n=350) living in British Columbia. A subset of BCC3 participants will be past participants of CARMA, n≥1000 women and children living with and without HIV, 2008-2018 and/or CHIWOS, n=1422 WLWH, 2013-2018. Over two study visits, we will collect biological specimens for virus serologies, hormones and biological markers as well as administer a survey capturing demographic and sociostructural-behavioural factors. Sociodemographics, comorbidities, number and type of chronic/latent viral infections and hormonal irregularities will be compared between the two groups. Their association with biological markers and psychostructural and sociostructural factors will be investigated through multivariable regression and structural equation modelling. Retrospective longitudinal analyses will be conducted on data from past CARMA/CHIWOS participants. As BCC3 aims to follow participants as they age, this protocol will focus on the first study visits. ETHICS AND DISSEMINATION: This study has been approved by the University of British Columbia Children's and Women's Research Ethics Board (H19-00896). Results will be shared in peer-reviewed journals, conferences and at community events as well as at www.hivhearme.ca and @HIV_HEAR_me. WLWH are involved in study design, survey creation, participant recruitment, data collection and knowledge translation. A Community Advisory Board will advise the research team throughout the study.

Elevated Blood Mitochondrial DNA in Early Life Among Uninfected Children Exposed to Human Immunodeficiency Virus and Combination Antiretroviral Therapy in utero.

BACKGROUND: Combination 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. METHODS: Whole-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. RESULTS: At 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. CONCLUSION: The 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.

Association of outcomes in acute flaccid myelitis with identification of enterovirus at presentation: a Canadian, nationwide, longitudinal study.

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.

Predictive value of repeated cerebrospinal fluid parameters in the outcomes of bacterial meningitis in infants <90 days of age.

BACKGROUND: There are variations in recommendations from different guidelines regarding the indications for repeat lumbar puncture (LP) in young infants with the diagnosis of bacterial meningitis. OBJECTIVE: To evaluate the frequency of repeat LPs and the characteristics of cerebrospinal fluid (CSF) parameters in repeated sampling and their predictive values for adverse outcomes in a national cohort. METHODS: This cohort study included infants born January 1, 2013 through December 31, 2014, who had proven or suspected bacterial meningitis within the first 90 days of life at seven paediatric tertiary care hospitals across Canada, and who underwent a repeat LP at the discretion of the treating physicians. RESULTS: Forty-nine of 111 infants (44%) underwent repeat LP at a median of 5 (IQR: 3, 13) days after the LP that led to the diagnosis of bacterial meningitis. Those who had meningitis caused by gram negative bacilli were more likely to have repeat LP than those with gram positive bacteria (77% versus 57%; p = 0.012). White blood cell (WBC) count on the second spinal tap yielded an area under the curve of 0.88 for predicting sequelae of meningitis at discharge from the hospital, with a cut-off value of 366 × 106/L, providing a sensitivity of 91% and specificity of 88%. CONCLUSION: In this multi-centre retrospective cohort study, infants with gram negative meningitis were more likely to have repeated LP. A high WBC on the second CSF sample was predictive of adverse outcome at the time of discharge from the hospital.

Inverse relationship between leukocyte telomere length attrition and blood mitochondrial DNA content loss over time.

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.

Enteroviral and herpes simplex virus central nervous system infections in infants < 90 days old: a Paediatric Investigators' Collaborative Network on Infections in Canada (PICNIC) study.

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 < 90 days of age with CNS infection proven to be due to enterovirus (EV) or herpes simplex virus (HSV) January 1, 2013 through December 31, 2014. 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 < 0.001). Unfavorable outcome occurred in 12 cases (11% of all EV and HSV infections) but was more likely following HSV than EV infection (4 (57%) versus 8 (8%); 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.

Transition from Pediatric to Adult HIV Care for Young Women Living with HIV.

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.