Short Cervix Following Initial Cerclage-Reinforcing Cerclage Versus Expectant Management.

OBJECTIVES: To determine whether reinforcing cerclage following ultrasound evidence of cerclage failure before 24 weeks is an effective method to delay gestational age at delivery, and to decrease the rate of preterm and peri-viable delivery. METHODS: A retrospective review was conducted for all patients who underwent any cervical cerclage procedure at a single tertiary care centre in Toronto, Canada between 1 December 2007 and 31 December 2017. RESULTS: Of 1482 cerclage procedures completed during the study period, 40 pregnant persons who underwent reinforcing cerclage were compared with 40 pregnant persons who were found to have cerclage failure before 24 weeks but were managed expectantly. After adjusting for the shortest cervical length measured prior to 24 weeks, there was no significant difference between the reinforcing cerclage and control group for gestational age at delivery, preterm, or peri-viable birth (P = 0.52, P = 0.54, P = 0.74, respectively). In an unadjusted model, there was a statistically significant increase in placental infection identified on postpartum placenta pathology in the reinforcing cerclage group compared with the expectant management group, 92.9% compared with 66.7% (P = 0.028). CONCLUSION: Reinforcing cerclage is unlikely to successfully delay the gestational age at delivery and reduce rates of preterm and pre-viable birth, especially if irreversible and progressive cervical change has begun. Future work should examine the role of preoperative amniocentesis to explore the impact of pre-existing intra-amniotic infection and reinforcing cerclage success.

Decentralized study of COVID Vaccine Antibody Response (STOPCoV): Results of a participant satisfaction survey.

The Covid-19 pandemic required many clinical trials to adopt a decentralized framework to continue research activities during lock down restrictions. The STOPCoV study was designed to assess the safety and efficacy of Covid-19 vaccines in those aged 70 and above compared to those aged 30-50 years of age. In this sub-study we aimed to determine participant satisfaction for the decentralized processes, accessing the study website and collecting and submitting study specimens. The satisfaction survey was based on a Likert scale developed by a team of three investigators. Overall, there were 42 questions for respondents to answer. The invitation to participate with a link to the survey was emailed to 1253 active participants near the mid-way point of the main STOPCoV trial (April 2022). The results were collated and answers were compared between the two age cohorts. Overall, 70% (83% older, 54% younger cohort, no difference by sex) responded to the survey. The overall feedback was positive with over 90% of respondents answering that the website was easy to use. Despite the age gap, both the older cohort and younger cohort reported ease of performing study activities through a personal electronic device. Only 30% of the participants had previously participated in a clinical trial, however over 90% agreed that they would be willing to participate in future clinical research. Some difficulties were noted in refreshing the browser whenever updates to the website were made. The feedback attained will be used to improve current processes and procedures of the STOPCoV trial as well as share learning experiences to inform future fully decentralized research studies.

COVID-19 vaccine antibody responses in community-dwelling adults to 48 weeks post primary vaccine series.

We report a decentralized prospective cohort study of self-reported adverse events and antibody responses to COVID vaccines derived from dried blood spots. Data are presented for 911 older (aged >70 years) and 375 younger (30-50 years) recruits to 48 weeks after the primary vaccine series. After a single vaccine, 83% younger and 45% older participants had overall seropositivity (p < 0.0001) increasing to 100/98% with the second dose, respectively (p = 0.084). A cancer diagnosis (p = 0.009), no mRNA-1273 vaccine doses (p <0 .0001), and older age (p <0 .0001) predicted lower responses. Antibody levels declined in both cohorts at 12 and 24 weeks increasing with booster doses. At 48 weeks, for participants with 3 vaccine doses, the median antibody levels were higher in the older cohort (p = 0.04) with any dose of mRNA-1273 (p <0 .0001) and with COVID infection (p <0 .001). The vaccines were well tolerated. Breakthrough COVID infections were uncommon (16% older cohort, 29% younger cohort; p < 0.0001) and mild.

Risk factors for unplanned paediatric intensive care unit admission after anaesthesia-an international multicentre study.

Objectives: Unplanned intensive care unit (ICU) admissions are associated with near-miss events, morbidity, and mortality. We describe the rate, resource utilization, and outcomes of paediatric patients urgently admitted directly to ICU post-anaesthesia compared to other sources of unplanned ICU admissions. Methods: We performed a secondary analysis of data from specialist paediatric hospitals in 7 countries. Patients urgently admitted to the ICU post-anaesthesia were combined and matched with 1 to 3 unique controls from unplanned ICU admissions from other locations by age and hospital. Demographic, clinical, and outcome variables were compared using the Wilcoxon rank-sum test for continuous variables and chi-square or Fisher's exact test for categorical variables. The effect of admission sources on binary outcomes was estimated using univariable conditional logistic regression models with stratification by matched set of anaesthesia and non-anaesthesia admission sources. Results: Most admissions were <1 year of age and for respiratory reasons. Admissions post-anaesthesia were shorter, occurred later in the day, and were more likely to be mechanically ventilated. Admissions post-anaesthesia were less likely to have had a previous ICU admission (4.8% compared to 11%, P=0.032) or PIM 'high-risk diagnosis' (9.5% versus 17.2%, P=0.035) but there was no difference in the number of subsequent ICU admissions. There was no difference in the PIM severity of illness score and no mortality difference between the groups. Conclusions: Young children and respiratory indications dominated unplanned ICU admissions post-anaesthesia, which was more likely later in the day and with mechanical ventilation.

What are we missing? The quality of intraoperative handover before and after introduction of a checklist.

PURPOSE: Intraoperative handovers are common in anesthesia practice and are associated with increased patient morbidity and mortality. Checklists may improve transfer of information during handovers. This before-and-after study sought to examine the effect of a checklist on intraoperative handover. We hypothesized that introducing a handover checklist would improve our primary outcome of completeness of data transfer. METHODS: From February to August 2016, anesthesia providers (residents, fellows, and consultants) at a single tertiary academic center participated in a handover study. Baseline handovers between anesthesia care providers were videotaped, analyzed, and compared with anesthetic records. An intraoperative handover checklist was then introduced, and handovers completed with it were videotaped. The completeness of handovers was compared between the baseline routine and checklist groups. The primary outcome was completeness of information transfer. RESULTS: Sixty-seven anesthesia providers participated in the study. Use of the intraoperative handover checklist improved completeness of handover by 6% (95% confidence interval [CI], 2 to 10; P < 0.01). There was no relationship observed between the provider (consultants/fellows vs resident) of the handovers and the degree of completeness (95% CI, 3 to 8; P = 0.33). Complexity had a significant impact on the handover completeness with low or high complexity cases more completely handed over than those of medium complexity both before and after the intervention-a 6% increase for low complexity (95% CI, 1 to 11; P = 0.02) and a 9% increase for high complexity (95% CI, 3 to 14; P < 0.01). CONCLUSION: Use of a checklist during intraoperative handovers improved completeness of data transfer. Handover checklists should be considered to improve handover completeness.

RéSUMé: OBJECTIF: Les transferts peropératoires sont fréquents dans la pratique de l'anesthésie et sont associés à une augmentation de la morbidité et de la mortalité des patients. Les listes de vérification pourraient améliorer le transfert d'informations pendant les transitions. Cette étude avant-après a cherché à examiner l'effet d'une liste de vérification sur les transferts peropératoires. Nous avons émis l'hypothèse que l'introduction d'une liste de vérification de transfert améliorerait notre critère d'évaluation principal, nommément la complétude du transfert des informations. MéTHODE: De février à août 2016, des prestataires d'anesthésie (résidents, fellows et consultants) d'un seul centre universitaire tertiaire ont participé à une étude sur les transferts. Les transferts de base entre les fournisseurs de soins d'anesthésie ont été filmés, analysés et comparés aux dossiers d'anesthésie. Une liste de contrôle de transfert peropératoire a ensuite été introduite, et les transferts réalisés avec celle-ci ont été filmés. La complétude des transferts a été comparée entre les groupes faisant un transfert normal de base et ceux utilisant la liste de vérification. Le critère d'évaluation principal était la complétude du transfert d'informations. RéSULTATS: Soixante-sept fournisseurs d'anesthésie ont participé à l'étude. L'utilisation de la liste de vérification de transfert peropératoire a amélioré la complétude du transfert de 6 % (intervalle de confiance [IC] à 95 %, 2 à 10; P < 0,01). Aucune relation n'a été observée entre le fournisseur (consultants/fellows) vs résidents) responsable des transferts et le degré de complétude du transfert (IC 95 %, 3 à 8; P = 0,33). La complexité a eu un impact significatif sur la complétude du transfert, les cas de basse ou haute complexité étant transférés de manière plus complète que les cas de complexité moyenne, tant avant qu'après l'intervention ­ avec une augmentation de 6 % pour les cas de faible complexité (IC 95 %, 1 à 11; P = 0,02) et une augmentation de 9 % pour les cas de complexité élevée (IC 95 %, 3 à 14; P < 0,01). CONCLUSION: L'utilisation d'une liste de vérification lors des transferts peropératoires a amélioré la complétude du transfert des informations. Les listes de vérification de transfert devraient être envisagées pour améliorer la complétude des transferts.

COVID-19 breakthrough infections in vaccinated participants of the Safety and Efficacy of Preventative COVID Vaccines sub-study.

BACKGROUND: The rate of breakthrough infection in vaccinated Ontarians during the Omicron wave is unknown. METHODS: Active participants of the Safety and Efficacy of Preventative COVID Vaccines (STOPCoV) study (892 ≥age 70 years and 369 aged 30-50 years) were invited to participate in a sub-study evaluating breakthrough COVID-19 infection. Self-administered rapid antigen tests (RAT) were reported twice weekly and symptom questionnaires weekly for 6 weeks. The primary outcome was the proportion reporting a positive RAT. RESULTS: A total of 806 e-consented, and 727 (90%) completed ≥1 RAT, with total 7,116 RATs completed between January 28 and March 29, 2022. Twenty out of twenty-five participants with a positive RAT had a booster vaccine prior to the positive test. All cases were mild, none requiring hospitalization. Nineteen had positive dried blood spot analysis for IgG antibody to the receptor binding domain (RBD) prior to the positive RAT. The mean normalized IgG ratio to RBD was 1.22 (SD 0.29) for younger and 0.98 (SD 0.44) for older participants, values similar to corresponding ratios for those without positive RATs and those in the main cohort. One hundred and five participants reported one and 96 reported ≥2 possible COVID-19 symptoms despite negative RATs. The false negative RAT was low (4% to 6.6 %) compared with subsequent positive nucleoprotein antibody. CONCLUSIONS: Positive RAT for COVID-19 was infrequent (3.4%). We were unable to determine a protective antibody level against breakthrough infection. Our findings can inform public health COVID-19 restrictions guidelines. Our decentralized study provides a model for rapid institution of new questions during a pandemic.

HISTORIQUE: On ne connaît pas le taux d'infections postvaccinales pendant la vague Omicron chez les Ontariens vaccinés. MÉTHODOLOGIE: Les participants actifs de l'étude Safety and Efficacy of Preventative COVID Vaccines (STOPCoV; 892 de 79 ans ou plus et 369 de 30 à 50 ans) ont été invités à prendre part à une sous-étude évaluant les infections postvaccinales causées par la COVID-19. Les résultats des tests d'antigène rapides (TAR) autoadministrés ont été transmis deux fois par semaine et le questionnaire sur les symptômes, toutes les semaines pendant six semaines. Les résultats primaires correspondaient à la proportion ayant déclaré des TAR positifs. RÉSULTATS: Au total, 806 ont consenti par voie électronique et 727 (90 %) ont effectué au moins un TAR, pour un total de 7 116 TAR effectués entre le 28 janvier et le 29 mars 2022. Ainsi, 21 des 25 participants ayant obtenu un résultat positif au TAR avaient reçu une dose de rappel auparavant. Tous les cas étaient légers, et aucun n'a dû être hospitalisé. Dix-neuf ont obtenu une analyse des gouttes de sang séché positives aux anticorps des IgG du domaine de liaison des récepteurs (RBD) avant le résultat positif du TAR. L'écart-type moyen du ratio d'IgG normalisé au RBD était de 1,22 (ÉT = 0,29) pour les participants plus jeunes, et de 0,98 (ÉT = 0,44) chez les participants plus âgés, les valeurs étaient semblables aux ratios correspondants pour ceux dont le TAR n'était pas positif et ceux de la cohorte principale. Au total, 105 participants ont déclaré un symptôme possible de COVID-19 et 96 en ont déclaré au moins deux, malgré des résultats négatifs au TAR. Le taux de TAR faussement négatifs était faible (4 % à 6,6 %) par rapport à l'anticorps nucléoprotéique positif subséquent. CONCLUSIONS: Les résultats positifs des TAR à la COVID-19 étaient peu courants (3,4 %). Les chercheurs n'ont pas été en mesure de déterminer le taux d'anticorps protecteurs contre l'infection postvaccinale. Ces résultats peuvent éclairer les directives sur les restrictions sanitaires liées à la COVID-19. La présente étude décentralisée fournit un modèle pour l'adoption rapide de nouvelles questions pendant une pandémie.

Death and Dying in Hospitalized Pediatric Patients: A Prospective Multicenter, Multinational Study.

Background: For hospitalized children admitted outside of a critical care unit, the location, mode of death, "do-not-resuscitate" order (DNR) use, and involvement of palliative care teams have not been described across high-income countries. Objective: To describe location of death, patient and terminal care plan characteristics of pediatric inpatient deaths inside and outside the pediatric intensive care unit (PICU). Design: Secondary analysis of inpatient deaths in the Evaluating Processes of Care and Outcomes of Children in Hospital (EPOCH) randomized controlled trial. Setting/Subjects: Twenty-one centers from Canada, Belgium, the United Kingdom, Ireland, Italy, the Netherlands, and New Zealand. Measurement: Descriptive statistics were used to compare patient and terminal care plan characteristics. A multivariable generalized estimating equation examined if palliative care consult during hospital admission was associated with location of death. Results: A total of 365 of 144,539 patients enrolled in EPOCH died; 219 (60%) died in PICU and 143 (40%) died on another inpatient unit. Compared with other inpatient wards, patients who died in PICU were less likely to be expected to die, have a DNR or palliative care consult. Hospital palliative care consultation was more common in older children and independently associated with a lower adjusted odds (95% confidence interval) of dying in PICU [0.59 (0.52-0.68)]. Conclusion: Most pediatric inpatient deaths occur in PICU where patients were less likely to have a DNR or palliative care consult. Palliative care consultation could be better integrated into end-of-life care for younger children and those dying in PICU.

A pragmatic randomized trial of a primary care antimicrobial stewardship intervention in Ontario, Canada.

BACKGROUND: More than 90% of antibiotics are prescribed in primary care, but 50% may be unnecessary. Reducing unnecessary antibiotic overuse is needed to limit antimicrobial resistance. We conducted a pragmatic trial of a primary care provider-focused antimicrobial stewardship intervention to reduce antibiotic prescriptions in primary care. METHODS: Primary care practitioners from six primary care clinics in Toronto, Ontario were assigned to intervention or control groups to evaluate the effectiveness of a multi-faceted intervention for reducing antibiotic prescriptions to adults with respiratory and urinary tract infections. The intervention included provider education, clinical decision aids, and audit and feedback of antibiotic prescribing. The primary outcome was total antibiotic prescriptions for these infections. Secondary outcomes were delayed prescriptions, prescriptions longer than 7 days, recommended antibiotic use, and outcomes for individual infections. Generalized estimating equations were used to estimate treatment effects, adjusting for clustering by clinic and baseline differences. RESULTS: There were 1682 encounters involving 54 primary care providers from January until May 31, 2019. In intervention clinics, the odds of any antibiotic prescription was reduced 22% (adjusted Odds Ratio (OR) = 0.78; 95% Confidence Interval (CI) = 0.64.0.96). The odds that a delay in filling a prescription was recommended was increased (adjusted OR=2.29; 95% CI=1.37, 3.83), while prescription durations greater than 7 days were reduced (adjusted OR=0.24; 95% CI=0.13, 0.43). Recommended antibiotic use was similar in control (85.4%) and intervention clinics (91.8%, p=0.37). CONCLUSIONS: A community-based, primary care provider-focused antimicrobial stewardship intervention was associated with a reduced likelihood of antibiotic prescriptions for respiratory and urinary infections, an increase in delayed prescriptions, and reduced prescription durations. TRIAL REGISTRATION: clinicaltrials.gov ( NCT03517215 ).

Activation and gut-homing of peripheral T cells in HIV immunologic non-responders despite long term viral suppression.

OBJECTIVE: Serious non-AIDS disease events (SNAE) are experienced disproportionately by immunologic non-responders (INRs), HIV-infected individuals who do not restore CD4 T cells in blood despite effective viral suppression. We aimed to characterize the inflammatory biomarker profile of the INR phenotype. METHODS: Blinded cross-sectional cohort study comparing markers of immune activation and gut homing between INR and non-INR individuals. HIV-positive participants had HIV RNA suppression on antiretroviral therapy and were categorized as either INR (N = 36) or Clinical Responders ("CR"; CD4>350/mm3; N = 47). 18 HIV-negative comparator individuals were included. Cellular markers were assessed by flow cytometry, with soluble markers assessed by ELISA and LC/MS-MS. Multivariable linear regression models estimated the association between INR phenotype and markers, adjusting for age, sex, duration of ART, and recent infection/vaccination. RESULTS: INR participants demonstrated a reduced CD4/CD8 ratio (p<0.001), 35% more CD8 activation (p = 0.02), 36% greater α4ß7+ CD4 T cells (p<0.01), 54% more HLA-DR+ CD4 T cells (p<0.001), and 20% higher plasma VCAM (p<0.01) compared to CRs. The INR phenotype was not associated with levels of Kyn/Trp, CRP, TNF, IFNγ, IL-8, IL-6, sCD14, D-Dimer, I-FABP, MCP-1, ICAM or CD8%HLA-DR+. CONCLUSIONS: Peripheral CD4 non-recovery during long-term treated HIV infection is characterized by elevated CD8 activation and CD4 gut homing. Gut-focused interventions may be warranted in the INR context, and CD8 activation may serve as a surrogate endpoint for clinical interventions.

Intimate partner and client-perpetrated violence are associated with reduced HIV pre-exposure prophylaxis (PrEP) uptake, depression and generalized anxiety in a cross-sectional study of female sex workers from Nairobi, Kenya.

INTRODUCTION: UNAIDS has identified female sex workers (FSW) as a key HIV at-risk population. FSW disproportionately experience gender-based violence, which compounds their risk of HIV acquisition and may contribute to adverse mental health outcomes. Pre-exposure prophylaxis (PrEP) is a powerful but underused HIV prevention tool for these women. This study explored the associations between intimate partner violence (IPV) and client-perpetrated violence against FSW, mental health outcomes and PrEP use. METHODS: An anonymous questionnaire was administered to a convenience sample of 220 Nairobi FSW attending dedicated clinics from June to July 2019, where PrEP was available free of charge. A modified version of the WHO Violence Against Women Instrument assessed IPV and client-perpetrated violence, and the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) assessed depressive and anxiety symptoms respectively. Multivariable logistic regressions evaluated predictors of depression, generalized anxiety and PrEP use. RESULTS: Of the total 220 women (median [IQR] age 32 [27-39]), 56.8% (125/220) reported depression (PHQ-9 ≥ 10) and 39.1% (86/220) reported anxiety (GAD-7 ≥ 10). Only 41.4% (91/220) reported optimal use of PrEP (taken correctly six to seven days/week) despite the cohort pursuing sex work for a median of 7 (4 to 12) years. Most women reported experiencing any violence in the past 12 months (90%, 198/220). Any recent IPV was frequent (78.7%, 129/164), particularly emotional IPV (66.5%, 109/164), as was any client-perpetrated violence in the past 12 months (80.9%, 178/220). Regression analyses found that violence was independently associated with depression (adjusted OR [aOR] 9.39, 95% CI 2.90 to 30.42, p = 0.0002) and generalized anxiety (aOR 3.47, 95% CI 1.10 to 10.88, p = 0.03), with the strongest associations between emotional IPV and both depression and anxiety. Recent client-perpetrated emotional violence (aOR 0.23, 95% CI 0.07 to 0.71, p = 0.01) was associated with decreased PrEP use, whereas client-perpetrated physical violence was associated with increased PrEP use (aOR 3.01, 95% CI 1.16 to 7.81, p = 0.02). CONCLUSIONS: There was a high prevalence of recent violence by different perpetrators as well as depression and anxiety among FSW from Nairobi. PrEP use was relatively infrequent, and recent client-perpetrated emotional violence was associated with PrEP non-use. Interventions to reduce gender-based violence may independently enhance HIV prevention and reduce the mental health burden in this community.

Increased CD4 : CD8 ratio normalization with implementation of current ART management guidelines.

OBJECTIVES: To determine the time to CD4 : CD8 ratio normalization among Canadian adults living with HIV in the modern ART era. To identify characteristics associated with ratio normalization. PATIENTS AND METHODS: Retrospective analysis of the Canadian Observational Cohort (CANOC), an interprovincial cohort of ART-naive adults living with HIV, recruited from 11 treatment centres across Canada. We studied participants initiating ART between 1 January 2011 and 31 December 2016 with baseline CD4 : CD8 ratio <1.0 and ≥2 follow-up measurements. Normalization was defined as two consecutive CD4 : CD8 ratios ≥1.0. Kaplan-Meier estimates and log-rank tests described time to normalization. Univariable and multivariable proportional hazards (PH) models identified factors associated with ratio normalization. RESULTS: Among 3218 participants, 909 (28%) normalized during a median 2.6 years of follow-up. Participants with higher baseline CD4+ T-cell count were more likely to achieve normalization; the probability of normalization by 5 years was 0.68 (95% CI 0.62-0.74) for those with baseline CD4+ T-cell count >500 cells/mm3 compared with 0.16 (95% CI 0.11-0.21) for those with ≤200 cells/mm3 (P < 0.0001). In a multivariable PH model, baseline CD4+ T-cell count was associated with a higher likelihood of achieving ratio normalization (adjusted HR = 1.5, 95% CI 1.5-1.6 per 100 cells/mm3, P < 0.0001). After adjusting for baseline characteristics, time-dependent ART class was not associated with ratio normalization. CONCLUSIONS: Early ART initiation, at higher baseline CD4+ T-cell counts, has the greatest impact on CD4 : CD8 ratio normalization. Our study supports current treatment guidelines recommending immediate ART start, with no difference in ratio normalization observed based on ART class used.

Deciphering the serological response to syphilis treatment in men living with HIV.

OBJECTIVE: To examine syphilis serology after treatment in people living with HIV. No unanimous guidelines exist in the era of increasing coinfection. DESIGN: Retrospective review using a tertiary care clinic in Toronto from 2000 to 2017. METHODS: The 2015 Centers for Diseases Control and Prevention syphilis guidelines were used to define an adequate serologic response. Cumulative distribution estimates and proportional hazards models accounting for interval censoring estimated the time to serologic response and seroreversion. Multistate models were used to investigate extended periods of serofast serology. RESULTS: A total of 171 patients with syphilis met our inclusion criteria (16 primary, 53 secondary, 26 early latent, 46 late latent, 30 neurosyphilis). Serologic response was achieved by 12 months for 65 (94%) patients and by 12-18 months for four (6%) patients with primary/secondary syphilis. For latent and neurosyphilis, 94 (92%) achieved serologic response by 24 months and one (1%) at 24.1 months. 84 (49%) patients achieved seroreversion with a median (95% confidence interval) time of 2 (1.44, 2.68) years. Latent syphilis was associated with a lower likelihood of achieving serologic response [hazard ratio (HR) = 0.52, P = 0.05] and seroreversion (HR = 0.27, P < 0.001) compared with primary/secondary syphilis. The probability of moving from a new infection state to a serofast state within 1 year was high (0.65) but the 1-year probability of transitioning from a serofast state to seroreversion was low (0.27). CONCLUSION: The majority of people living with HIV infected with syphilis will achieve an adequate serologic response as per the Centers for Diseases Control and Prevention guidelines. Seroreversion was observed in about half but can take years to occur.

Pilot study assessing the Rotterdam Healthy Aging Score in a cohort of HIV-positive adults in Toronto, Canada.

OBJECTIVE: The Rotterdam Healthy Aging Score (HAS) is a validated multidimensional index constructed from five health domains. We describe the HAS distribution in a cohort of HIV-positive adults and correlate it with health outcomes. DESIGN: A cross-sectional pilot study of 101 adults aged at least 40 years, on suppressive antiretroviral therapy attending a tertiary HIV clinic in Toronto, Canada. METHODS: Participants completed questionnaires to calculate their HAS (range 0-14). Demographics, HAS and sub-scores were compared by age and sex. The HAS was compared with results of the Fried Frailty Score, Short Performance Physical Battery score (SPPB) and measures of health utilization. Kruskal--Wallis Rank-Sum and Fisher's exact tests were used for all comparisons. RESULTS: Median (IQR) age was 56 (50--62), 81 (80%) men and 50 (50%) born in Canada. Median (IQR) CD4 cell count was 574 (417--794) cells/µl. Median (IQR) HAS was 12 (10--13) with 39 (39%) achieving a score more than 12 (considered healthy aging). Younger participants experienced more depression, whereas women had greater pain. The HAS score correlated with the Fried Frailty Score (P = 0.008) and trended with the SPPB Score (P = 0.077). Those with the poorest HAS scores were more likely to have been hospitalized in the preceding 6 months (P = 0.034). CONCLUSION: The HAS ranged from 5 to 14 in this cohort of older HIV adults with 39% attaining scores in the 'healthy' range. The HAS correlated with measures of physical performance and health utilization. Further validation of an objective outcome in HIV-positive patients will facilitate evaluation of interventional studies to improve healthy aging.

Inflammatory biomarker levels over 48 weeks with dual vs triple lopinavir/ritonavir-based therapy: Substudy of a randomized trial.

BACKGROUND: Inflammation has been associated with increased morbidity and mortality in HIV-positive patients. We compared inflammatory biomarkers with dual therapy using lopinavir/ritonavir plus lamivudine (LPV/r+3TC) versus triple therapy using LPV/r plus two nucleoside reverse transcriptase inhibitors (LPV/r+2NRTIs) in treatment-naïve HIV-positive adults. METHODS: This was a substudy among Argentinian participants in the randomized trial GARDEL. We measured hsCRP, IL-6, MCP-1, TNF, D-dimer and sCD14 from plasma collected at baseline, week 24 and week 48. Generalized estimating equations with an identity/logit link were used to model the average impact of dual versus triple therapy on each biomarker over time, controlling for baseline levels. Additional models estimated the average effect of virologic suppression on biomarker levels over time, adjusting for age, sex, and baseline CD4 count. RESULTS: Of 191 trial participants enrolled in Argentina, 172 had baseline and follow-up measurements and were included. Median (IQR) age was 35.5 (28.5, 45) years and CD4 cell count was 310 (219, 414) cells/mm3. Dual therapy was not associated with significantly different biomarker levels over 48 weeks relative to triple therapy. Virologic suppression was associated with statistically significant decreases in MCP-1, TNF and D-dimer levels and an unexpected increase in sCD14 levels. No change was observed in hsCRP or the proportion of participants with undetectable IL-6 levels. CONCLUSIONS: In addition to having virologic non-inferiority, LPV/r+3TC dual therapy is generally associated with similar inflammatory biomarker levels over 48 weeks compared to LPV/r+2NRTIs triple therapy in treatment-naïve adults. Further study of dual treatment regimens is warranted.

Tenofovir and emtricitabine resistance among antiretroviral-naive patients in the Canadian Observational Cohort Collaboration: implications for PrEP.

BACKGROUND: The real-world effectiveness of pre-exposure prophylaxis (PrEP) may be influenced by circulating HIV strains resistant to either tenofovir or emtricitabine. Yet, few studies have examined rates of resistance to these drugs in clinical settings. METHODS: We conducted a retrospective cohort study of antiretroviral-naive participants in the Canadian Observational Cohort collaboration who initiated antiretroviral therapy between 2006 and 2014. In separate analyses, we determined the prevalence of pretherapy resistance and cumulative incidence of follow-up resistance to tenofovir and emtricitabine. We used multivariable proportional hazards models to examine associations between baseline variables and the development of resistance. RESULTS: We studied 6,622 antiretroviral-naive participants initiating therapy, of whom 5,428 (82.0%) had a baseline resistance test. Baseline resistance to tenofovir and emtricitabine was observed in 83 (1.5%) and 21 (0.4%) patients, respectively. Among patients without baseline resistance, the cumulative incidence of resistance to tenofovir and emtricitabine 5 years following treatment initiation was 0.0070 (95% CI 0.0046, 0.0095) and 0.033 (95% CI 0.028, 0.038), respectively. Following multivariable analysis, a baseline viral load ≥100,000 copies/ml was associated with emergence of tenofovir (hazard ratio [HR] 2.88; 95% CI 1.35, 6.15) and emtricitabine (HR 2.27; 95% CI 1.64, 3.15) resistance. Initiating an integrase inhibitor-based regimen and CD4+ T-cell count below 200 cells/mm3 were also associated with resistance to each drug. CONCLUSIONS: We observed a low prevalence of baseline resistance and a low incidence of emergence of resistance to tenofovir and emtricitabine among antiretroviral-naive patients in routine clinical care.

Effect of valaciclovir on CD4 count decline in untreated HIV: an international randomized controlled trial.

Objectives: To determine the impact of valaciclovir on HIV disease progression in treatment-naive HIV-positive adults. Methods: In this fully blind, multicentre, 1:1 randomized placebo-controlled trial, treatment-naive HIV-1-positive adults with CD4 counts 400-900 cells/mm3 and not meeting contemporaneous recommendations for combination ART (cART) were randomized to valaciclovir 500 mg or placebo twice daily, and followed quarterly until having two consecutive CD4 counts ≤350 cells/mm3 or initiating cART for any reason. The primary analysis compared the rate of CD4 count decline by study arm after adjusting for baseline CD4 count and viral load (VL). Secondary analyses compared the rate of CD4 percentage decline, HIV VL, herpes simplex virus (HSV) recurrences and drug-related adverse events. The trial closed after release of the START trial results in August 2015. Results: We enrolled 198 participants in Canada, Brazil, Argentina and the UK. Median (IQR) age was 35 (30-43) years. Baseline CD4 count was 592 (491-694) cells/mm3 and VL was 4.04 (3.5-4.5) log10 copies/mL. Over 276 person-years of follow-up, CD4 counts declined by 49 cells/mm3/year in the valaciclovir arm versus 58 cells/mm3/year in the placebo arm (P = 0.65). No differences were seen in the rate of change in CD4 percentage (-1.2%/year versus -1.7%/year, P = 0.34). VL was 0.27 log10 copies/mL lower in valaciclovir participants overall (P<0.001). Placebo participants had more HSV recurrences (62 versus 21/100 person-years, P < 0.0001) but similar rates of grade ≥2 drug-related adverse events. Conclusions: Unlike prior trials using aciclovir, we found that valaciclovir did not slow CD4 count decline in cART-untreated adults, although power was limited due to premature study discontinuation. Valaciclovir modestly lowered HIV VL.

Acceptability and tolerability of and adherence to HIV preexposure prophylaxis among Toronto gay and bisexual men: a pilot study.

BACKGROUND: Preexposure prophylaxis is efficacious at preventing HIV infection, but concerns persist about adherence and sexually transmitted infections (STIs). We assessed preexposure prophylaxis acceptability, adherence and clinical outcomes in a pilot demonstration project. METHODS: HIV-uninfected adult gay and bisexual men who scored 10 or higher on a validated HIV risk score (HIV Incidence Risk Index for MSM) and reported condomless receptive anal sex were sequentially enrolled into a 1-year open-label single-arm pilot study of daily oral therapy with tenofovir disoproxil fumarate/emtricitabine in Toronto. The primary outcome was acceptability of preexposure prophylaxis. Secondary outcomes were preexposure prophylaxis adherence (4-d recall, pill count and dried blood spot analysis), HIV seroconversion, STIs and adverse events. RESULTS: Of the 86 men screened, 52 were enrolled. Participants were mostly young (median age 33 yr [interquartile range (IQR) 28-37 yr) white (38 [73%]) gay (49 [94%]) men. Preexposure prophylaxis acceptability was high: all participants reported their experience as "good" or "very good." The median adherence rate was high, at 100% (IQR 95%-100%) by self-report and 96.9% (IQR 93.4%-98.4%) by pill count. Dried blood spot analysis suggested that doses were taken 4-7 days/week at 88.7% (173/195) of month 3-12 visits. No cases of HIV seroconversion occurred, but 25 participants (48%) experienced at least 1 bacterial STI, with incidence rates per 100 person-years of 32.8, 32.8, 8.2 and 8.2 for chlamydia, gonorrhea, syphilis and lymphogranuloma venereum, respectively. No adverse events led to discontinuation of prophylaxis, but the estimated glomerular filtration rate declined by 0.22 mL/min per month. INTERPRETATION: Preexposure prophylaxis was associated with high adherence and acceptability and no HIV infections in this study. Frequent STIs and clinically unapparent toxic renal effects reinforce the need for ongoing vigilance. TRIAL REGISTRATION: ClinicalTrials. gov, no. NCT02149888.

High retention in HIV care at a tertiary care centre in Toronto, Canada.

Poor retention in HIV care is associated with poor clinical outcomes and mortality. Previous studies of predictors of poor retention have been conducted with a wide variety of populations, using different measures of retention, and occasionally have conflicting results. We studied demographic and psychosocial factors associated with inter-visit interval length in a setting of universal health care and modern cART. Patients attending ≥2 appointments with an HIV specialist at the Toronto General Hospital Immunodeficiency Clinic from 2004 to 2013 were studied. A sub-analysis included psychosocial measures from annual questionnaires for Ontario HIV Treatment Network Cohort Study (OCS) participants. Median inter-visit interval and constancy (percentage of 4-month intervals with ≥1 visit) were calculated by patient. Multivariable generalized estimating equation models identified factors associated with inter-visit interval length and intervals ≥12 months. 1591 patients were included. 615 patients completed an OCS questionnaire and were more likely to be older white MSM from Canada with a viral load (VL) <50 copies/ml. The median (IQR) of patients' median inter-visit intervals was 3.15 (2.78, 3.84) months and median (IQR) constancy was 90% (71%, 100%). Two percent of inter-visit intervals were ≥12 months and 25% of patients had ≥1 interval ≥12 months. Longer inter-visit intervals were associated with younger age, white race, earlier calendar year, longer duration of HIV, VL < 50 copies/mL and higher CD4 counts. Patients who were younger, white, had injection drug use as a risk factor, had a longer duration of HIV, and had VL ≥50 copies/mL were more likely to have an inter-visit interval ≥12 months. In the OCS sub-analysis including psychosocial variables, lower levels of depression were associated with longer inter-visit intervals. Retention at this tertiary care centre was high. Efforts to maximize attendance should focus on younger patients and those with substance abuse issues.

Comparison of atazanavir/ritonavir and darunavir/ritonavir based antiretroviral therapy for antiretroviral naïve patients.

BACKGROUND: Atazanavir/ritonavir and darunavir/ritonavir are common protease inhibitor-based regimens for treating patients with HIV. Studies comparing these drugs in clinical practice are lacking. METHODS: We conducted a retrospective cohort study of antiretroviral naïve participants in the Canadian Observational Cohort (CANOC) collaboration initiating atazanavir/ritonavir- or darunavir/ritonavir-based treatment. We used separate Fine and Gray competing risk regression models to compare times to regimen failure (composite of virologic failure or discontinuation for any reason). Additional endpoints included virologic failure, discontinuation due to virologic failure, discontinuation for other reasons, and virologic suppression. RESULTS: We studied 222 patients treated with darunavir/ritonavir and 1791 patients treated with atazanavir/ritonavir. Following multivariable adjustment, there was no difference between darunavir/ritonavir and atazanavir-ritonavir in the risk of regimen failure (adjusted hazard ratio 0.76, 95% CI 0.56 to 1.03) Darunavir/ritonavir-treated patients were at lower risk of virologic failure relative to atazanavir/ritonavir treated patients (aHR 0.50, 95% CI 0.28 to 0.91), findings driven largely by high rates of virologic failure among atazanavir/ritonavir-treated patients in the province of British Columbia. Of 108 discontinuations due to virologic failure, all occurred in patients starting atazanavir/ritonavir. There was no difference between regimens in time to discontinuation for reasons other than virologic failure (aHR 0.93; 95% CI 0.65 to 1.33) or virologic suppression (aHR 0.99, 95% CI 0.82 to 1.21). CONCLUSIONS: The risk of regimen failure was similar between patients treated with darunavir/ritonavir and atazanavir/ritonavir. Although darunavir/ritonavir was associated with a lower risk of virologic failure relative to atazanavir/ritonavir, this difference varied substantially by Canadian province and likely reflects regional variation in prescribing practices and patient characteristics.

Novel imaging modalities for the comparison of bone microarchitecture among HIV+ patients with and without fractures: a pilot study.

BACKGROUND: HIV-infected adults have increased fracture risk. OBJECTIVES: To generate pilot data comparing bone density, structure, and strength between HIV-infected adults with and without a prior fracture. METHODS: Adults with and without a prior fracture after their HIV diagnosis were matched 1:1 based on age, sex, race, and smoking history. Participants underwent dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS), hip structural analyses (HSA), vertebral fracture assessment (VFA), high-resolution peripheral quantitative tomography (HR-pQCT) and measurement of bone turnover markers. Results were compared between cases and controls, with differences expressed as percentages of control group values. RESULTS: 23 pairs were included. On DXA, cases had lower areal bone mineral density (aBMD) at the total hip (median difference in T-score -0.25, p = 0.04), but not the lumbar spine (median difference in T-score 0.10, p = 0.68). Cases had greater abnormalities in HSA and most HR-pQCT and HSA measures, by up to 15%. VFA revealed two subclinical fractures among cases but none among controls. TBS, CTX, and P1NP levels were similar between groups, with differences of 1.9% (p = 0.90), 9.7% (p = 0.55), and 10.0% (p = 0.24), respectively. For each parameter, we report the median and interquartile range for the absolute and relative difference between cases and controls, the correlation between cases and controls, and our recruitment rates, to inform the design of future studies. CONCLUSIONS: These pilot data suggest potential differences in bone structure, estimated bone strength, and asymptomatic vertebral fractures among HIV-infected adults with and without fracture, warranting further study as markers of fracture risk in HIV.