Mpox in people with past infection or a complete vaccination course: a global case series.

BACKGROUND: Since May, 2022, a large global outbreak of human mpox (formerly known as monkeypox) has predominantly affected men who have sex with men. The strain responsible, Clade IIb, has mutated substantially from precursors originating from the 2017-18 outbreak in Nigeria. Immunity to smallpox, another orthopoxvirus, via previous infection or vaccination provides lifelong immunity. However, since the 2022 mpox outbreak, recent clusters were described in individuals with presumed immunity through recent infection or vaccination. We aim to describe the epidemiological and clinical characteristics of mpox in individuals with past infection or vaccination to improve the understanding of this disease in the setting of previous immunity. METHODS: In this global case series, international collaborators from nine countries provided data on individuals with PCR-confirmed mpox after documented previous infection or vaccination between May 11, 2022, and June 30, 2023. We excluded cases that could not confirm vaccination status or cases with partial immunisation or any doses received before the current multi-national mpox outbreak (cutoff date May 1, 2022). Data were collected via a case report spreadsheet that reported on dates of infection and vaccination, route of immunisation, demographic characteristics, clinical findings, HIV status, concomitant sexually transmitted infections, and markers of disease severity (mpox severity score system). We describe case epidemiology, clinical course, and mpox severity scores; all analyses were descriptive. FINDINGS: We report mpox infections in 37 gay and bisexual men who have sex with men: seven individuals had mpox reinfections, 29 individuals had mpox infections that occurred after two appropriately spaced Modified Vaccinia Ankara-Bavarian Nordic vaccine courses, and one individual had an infection that met the criteria for both reinfection and infection after vaccination. The median age of individuals was 36 years (IQR 30-45; range 21-58). Those with natural immunity after initial infection had a shorter disease course with less mucosal disease upon reinfection than with their initial infection. Infections post-vaccination were characterised by few lesions, little mucosal disease, and minimal analgesia requirements; two people received oral tecovirimat. Overall, there were no deaths, no bacterial superinfections, and all individuals were managed in the ambulatory clinic with one hospital admission for a necrotising neck lesion. INTERPRETATION: The epidemiology of people with mpox reinfection or infection post-vaccination was similar to other published cohorts during the 2022 outbreak-predominantly young, sexually active gay and bisexual men who have sex with men. Clinical features and outcomes of repeat infection and infection after vaccination appear to be less clinically severe than those described in 2022 case literature. Specifically, compared with the 2022 case series, these individuals in the present study had fewer confluent lesions, less mucosal involvement, reduced analgesia requirement, and fewer admissions. Natural immunity and vaccine-induced immunity are not fully protective against mpox infection. However, in this small series both disease duration and severity appear to be reduced. FUNDING: None.

Exploring implementation considerations for geriatric-HIV clinics: A secondary analysis from a scoping review on HIV models of geriatric care.

OBJECTIVES: This review aimed to map the current state of knowledge regarding the implementation considerations of existing geriatric-HIV models of care, to identify areas of further research and to inform the implementation of future geriatric-HIV interventions that support older adults living with HIV. METHODS: We conducted a scoping review that was methodologically informed by the Arskey and O'Malley's 5 step framework and theoretically informed by the Consolidated Framework for Implementation Research (CFIR). A systematic search of six databases was conducted for peer-reviewed literature. The grey literature was also searched. Article screening was performed in duplicate. Data was extracted for the purpose of this secondary analysis using a data extraction template informed by the CFIR. Data was inductively and deductively analyzed. RESULTS: In total, 11 articles met the inclusion criteria. The models of care described varied in terms of their location and setting, the number and type of care providers involved, the mechanism of patient referral, the type of assessments and interventions performed and the methods of longitudinal patient follow-up. Four key categories emerged to describe factors that influenced their implementation: care provider buy-in, patient engagement, mechanisms of communication and collaboration, and available resources. CONCLUSIONS: The findings from this scoping review provide an initial understanding of the key factors to consider when implementing geriatric-HIV models of care. We recommend health system planners consider mechanisms of communication and collaboration, opportunities for care provider buy-in, patient engagement and available resources. Future research should explore implementation in more diverse settings to understand the nuances that influence implementation and care delivery.

Role of fatty liver in the epidemic of advanced chronic liver disease among people with HIV: protocol for the Canadian LIVEHIV multicentre prospective cohort.

INTRODUCTION: Advanced chronic liver disease (ACLD) is a major cause of death for people with HIV (PWH). While viral hepatitis coinfections are largely responsible for this trend, metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging concern for PWH. We aimed to assess the contribution of MASLD to incident ACLD in PWH. METHODS AND ANALYSIS: This multicentre prospective observational cohort study will enrol 968 consecutive HIV monoinfected patients from four Canadian sites, excluding subjects with alcohol abuse, liver disease other than MASLD, or ACLD at baseline. Participants will be followed annually for 4 years by clinical evaluation, questionnaires, laboratory testing and Fibroscan to measure liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). The primary outcome will be incidence of ACLD, defined as LSM>10 kPa, by MASLD status, defined as CAP≥285 dB/m with at least one metabolic abnormality, and to develop a score to classify PWH according to their risk of ACLD. Secondary outcomes will include health-related quality of life (HRQoL) and healthcare resource usage. Kaplan-Meier survival method and Cox proportional hazards regression will calculate the incidence and predictors of ACLD, respectively. Propensity score methods and marginal structural models will account for time-varying exposures. We will split the cohort into a training set (to develop the risk score) and a validation set (for validation of the score). HRQoL scores and healthcare resource usage will be compared by MASLD status using generalised linear mixed effects model. ETHICS AND DISSEMINATION: This protocol has been approved by the ethics committees of all participating institutions. Written informed consent will be obtained from all study participants. The results of this study will be shared through scientific publications and public presentations to advocate for the inclusion of PWH in clinical trials of MASLD-targeted therapies and case-finding of ACLD in PWH.

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.

Cognitive screening considerations for psychosocial clinical trials in HIV, aging, and cognition.

Cognitive impairment is a common comorbidity among individuals aging with HIV, which can be an extreme source of stress and anxiety for many. Psychosocial interventions have the potential to alleviate symptoms associated with cognitive impairment and help improve the quality of life of people with HIV as they continue to age; these interventions are in the infancy of development and require further testing via clinical trials. The slow development of interventions may be partially attributed to a common trend of requiring a formal HIV-associated neurocognitive disorder diagnosis to qualify for psychosocial clinical trials. HIV-associated neurocognitive disorder is diagnosed through intensive, time-consuming tests, and still many cases of HIV-associated neurocognitive disorder remain undiagnosed, misdiagnosed, or misclassified due to the limitations of the assessment process. This commentary suggests an alternate method of screening for cognitive impairments through the use of a brief, low-barrier assessment, alongside validity considerations. Such alternate screening may improve enrollment and completion rates in psychosocial clinical trials for people aging with HIV and cognitive impairment, by removing the burden of extensive testing that is commonly associated with an HIV-associated neurocognitive disorder diagnosis from clinical trial eligibility, while still providing valuable insight into individuals' cognitive functioning.

"We can hardly even do it nowadays. So, what's going to happen in 5 years from now, 10 years from now?" The health and community care and support needs and preferences of older people living with HIV in Ontario, Canada: a qualitative study.

INTRODUCTION: The population of people living with HIV (PLWH) is ageing consequent to effective treatment and a steady stream of new diagnoses among older adults. PLWH experience a greater burden of age-related comorbidities and poorer social determinants of health compared to their HIV-negative peers, yet comprehensive requisites for care and support as PLWH age remain poorly understood. Preferences And Needs for Ageing Care among HIV-positive Elderly people in Ontario, Canada (PANACHE ON), explored the health and community care and social support needs and preferences of a diverse group of older PLWH (age 60+) and described life course experiences among older PLWH that shape these needs and preferences and whether they are met. METHODS: PANACHE ON was a qualitative community-based participatory research study. In-person focus groups using a semi-structured interview guide were co-facilitated by pairs of trained older PLWH from July to October 2019. Purposive sampling bolstered the inclusion of communities disproportionately affected by HIV in Ontario. Descriptive analysis was used to summarize demographic data; participatory data analysis was conducted by a subset of the research team, with transcripts double-coded and analysed using NVIVO 12 Plus. RESULTS: A total of 73 PLWH participated, 66% identified as men. The mean age was 64 years (range 55-77) and median time living with HIV was 23 years (range 2-37). The current and anticipated needs of older PLWH, many of which were only partially met, included necessities such as food and housing, mobility and sensory aids, in-home support, social and emotional support, transportation and information. Three experiences-trauma, stigma and uncertainty-intersected in the lives of many of our participants, shaping their needs for care and support, and impacting the ease with which these needs were met. CONCLUSIONS: Unmet health and social needs and limited control over the availability and accessibility of ageing-related care and support due to resource constraints or reduced capacity for self-advocacy results in anxiety about the future among older PLWH, despite their well-developed coping strategies and experience navigating systems of care. These study findings will inform the development of the first national needs assessment of older PLWH in Canada.

A randomized control trial of high-dose micronutrient-antioxidant supplementation in healthy persons with untreated HIV infection.

BACKGROUND: Although micronutrient and antioxidant supplementation are widely used by persons with human immunodeficiency virus (HIV), a therapeutic role beyond recommended daily allowances (RDA) remains unproven. An oral high-dose micronutrient and antioxidant supplement (Treatment) was compared to an RDA supplement (Control) for time to progressive immunodeficiency or initiation of antiretroviral therapy (ART) in people living with HIV (PLWH). METHODS: This study was a randomized, double-blind, placebo-controlled multicenter clinical trial. PLWH were recruited from Canadian HIV Trials Network sites, and followed quarterly for two years. Eligible participants were asymptomatic, antiretroviral treatment (ART)-naïve, HIV-seropositive adults with a CD4 T lymphocyte count (CD4 count) between 375-750 cells/µL. Participants were randomly allocated 1:1 to receive Treatment or Control supplements. The primary outcome was a composite of time-to-first of confirmed CD4 count below 350 cells/µL, initiation of ART, AIDS-defining illness or death. Primary analysis was by intention-to-treat. Secondary outcomes included CD4 count trajectory from baseline to ART initiation or two years. A Data and Safety Monitoring Board reviewed the study for safety, recruitment and protocol adherence every six months. RESULTS: Of 171 enrolled participants: 66 (38.6%) experienced a primary outcome: 27 reached a CD4 count below 350 cells/µL, and 57 started ART. There was no significant difference in time-to-first outcome between groups (Hazard Ratio = 1.05; 95%CI: 0.65, 1.70), or in time to any component outcome. Using intent-to-treat censoring, mean annualized rates of CD4 count decline were -42.703 cells/µL and -79.763 cells/µL for Treatment and Control groups, with no statistical difference in the mean change between groups (-37.06 cells/µL/52 weeks, 95%CI: (-93.59, 19.47); p = 0.1993). Accrual was stopped at 171 of the 212 intended participants after an interim analysis for futility, although participant follow-up was completed. CONCLUSIONS: In ART-naïve PLWH, high-dose antioxidant, micronutrient supplementation compared to RDA supplementation had no significant effect on disease progression or ART initiation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00798772.

Use of Systemic Therapies for Treatment of Psoriasis in People Living with Controlled HIV: Inference-Based Guidance from a Multidisciplinary Expert Panel.

BACKGROUND: People living with human immunodeficiency virus (PLHIV) have a similar prevalence of psoriasis as the general population, though incidence and severity correlate with HIV viral load. Adequately treating HIV early renders the infection a chronic medical condition and allows PLHIV with a suppressed viral load (PLHIV-s) to live normal lives. Despite this, safety concerns and a lack of high-level data have hindered the use of systemic psoriasis therapies in PLHIV-s. OBJECTIVES: We aim to provide a structured framework that supports healthcare professionals and patients discussing the risks and benefits of systemic psoriasis therapy in PLHIV-s. Our goal was to address the primary question, are responses to systemic therapies for the treatment of psoriasis in PLHIV-s similar to those in the non-HIV population? METHODS: We implemented an inference-based approach relying on indirect evidence when direct clinical trial data were absent. In this instance, we reviewed indirect evidence supporting inferences on the status of immune function in PLHIV. Recommendations on systemic treatment for psoriasis in PLHIV were derived using an inferential heuristic. RESULTS: We identified seven indirect indicators of immune function informed by largely independent bodies of evidence: (1) functional assays, (2) vaccine response, (3) life expectancy, (4) psoriasis manifestations, (5) rate of infections, (6) rate of malignancies, and (7) organ transplant outcomes. CONCLUSIONS: Drug-related benefits and risks when treating a patient with systemic psoriasis therapies are similar for non-HIV patients and PLHIV with a suppressed viral load and normalized CD4 counts. Prior to initiating psoriasis treatment in PLHIV, HIV replication should be addressed by an HIV specialist. Exercise additional caution for patients with a suppressed viral load and discordant CD4 responses on antiretroviral therapy.

People living with human immunodeficiency virus (PLHIV) develop psoriasis as often as everyone else. We asked: what are effective and safe treatments when PLHIV need systemic therapy (pills or injections) for their psoriasis?HIV infection attacks the immune system. When HIV is not treated, the immune system declines. A less effective immune system makes it harder for the body to fight infections and certain cancers. Psoriasis is a skin condition caused by overactive immune cells. Effective psoriasis treatments reduce immune-cell activity. There are some concerns that treatments for psoriasis may not work and could worsen infections or cancers.To answer the question, we gathered 11 dermatologists and 4 HIV specialists. We reviewed the international scientific literature on PLHIV and psoriasis. The absence of direct evidence and volume of information to review made the process challenging. The end results were worthwhile.We concluded that people who are diagnosed early and take antiretroviral therapy to control their HIV infection (PLHIV-c) can live long, healthy lives. Accordingly, we determined that PLHIV-c can likely expect the same safety and efficacy for systemic psoriasis treatments as the general population. Treatment decisions should be made on a case-by-case basis through consultation with the patient and treating physician(s).Pillars of modern medicine are evidence-based care and collaborative decision-making. Too often, neither care provider nor patient are adequately informed. We have tried to fill one information gap for PLHIV and psoriasis. This process may help answer questions in other disease populations where direct evidence is scarce or absent.

Neighbourhood-level material deprivation and response to combination antiretroviral therapy in the Canadian Observational Cohort (CANOC): a longitudinal cohort study.

BACKGROUND: Socioeconomic status has been associated with higher viral loads and lower CD4 cell counts among people living with HIV. The objective of this study was to evaluate the relation between neighbourhood-level material deprivation and immunologic and virologic response to combination antiretroviral therapy (ART) among people living with HIV in Canada. METHODS: The Canadian Observational Cohort (CANOC) is a longitudinal cohort of people living with HIV, containing data from 2000-2016 from 5 Canadian provinces. We defined response to combination ART as positive if the CD4 cell count increased by 50 cells/mm3 (0.05 cells × 109/L) or more (CD4+) and viral load decreased to 50 copies/mL or less (VL+) within 6 months of treatment initiation. We further categorized response to therapy as concordant positive (CD4+/VL+), concordant negative (CD4-/VL-) or discordant (CD4+/VL- or CD4-/VL+). We used adjusted multinomial logistic regression to quantify the relation between neighbourhood-level material deprivation and immunologic and virologic response. RESULTS: This study included 8274 people living with HIV, of which 1754 (21.2%) lived in the most materially deprived neighbourhoods. Most individuals (62.2%) showed a concordant positive response to combination ART. After adjustment, living in the most materially deprived neighbourhoods was associated with a CD4-/VL+ discordant response (adjusted odds ratio [OR] 1.31, 95% confidence interval [CI] 1.06-1.62) and a concordant negative response (adjusted OR 1.45, 95% CI 1.13-1.86), using a concordant positive response as the reference. No other deprivation quartile was independently associated with a particular response. INTERPRETATION: People living with HIV from the most materially deprived neighbourhoods had increased odds of poor immunologic or virologic response to combination ART. These results motivate further study of the specific socioeconomic factors that potentially affect response to combination ART among people living with HIV in Canada.

Randomized, Blinded, Placebo-Controlled Trial of De Simone Formulation Probiotic During HIV-Associated Suboptimal CD4+ T Cell Recovery.

OBJECTIVE: To assess whether probiotic supplementation may reduce disease-linked systemic immune activation in people living with HIV with the immunologic nonresponder phenotype. DESIGN: Phase 2b, randomized, double-blind, placebo-controlled pilot trial. METHODS: HIV-positive individuals with blood CD4+ T-cell counts <350/mm3 despite viral suppression were randomized to 2:1 to receive De Simone Formulation Probiotic (DSFP; "Visbiome" commercially) or placebo for 48 weeks; target enrollment was 36 patients. The primary endpoint was the change in blood CD8+ T-cell coexpression of human leukocyte antigen-DR isotype and CD38 ("CD8 activation"). Secondary endpoints included biomarkers of inflammation, immune reconstitution, bacterial translocation, and gut permeability. Adjusted linear regression and linear mixed regression methods evaluated the differences between study arms from baseline to week 48. Study monitoring was performed by the CIHR Canadian HIV Trials Network Data Safety Monitoring Committee. RESULTS: Nineteen patients received DSFP, whereas 10 received placebo. One probiotic arm patient withdrew early. Blood CD8 activation increased 0.82 percentage points (pp) in the probiotic arm (95% confidence interval: -1.23 to 2.87;) and decreased by 2.06 pp in the placebo arm (-4.81 to 0.70; between arms P = 0.097). CD4+ T-cell activation (%HLA-DR+) decreased in the placebo arm [-3.79 pp (-7.32 to -0.26)] but increased in the probiotic arm [1.64 (-0.98 to 4.26); between arms P = 0.018]. No differences were observed in plasma or urine biomarkers of inflammation or microbial translocation. CONCLUSIONS: Blood immune activation markers in immunologic nonresponder individuals on effective antiretroviral treatment were not reduced by supplementation with DSFP; CD4+ T-cell activation may have been increased.

The Dietary Inflammatory Index Is Not Associated With Gut Permeability or Biomarkers of Systemic Inflammation in HIV Immunologic Non-responders.

Immunologic non-responders (INRs) are a subset of individuals living with HIV who have suboptimal blood CD4+ T cell recovery despite effective antiretroviral therapy (ART). They are at an increased risk of serious non-AIDS co-morbidities and death, and demonstrate enhanced systemic immune activation. In other populations diet has been correlated with markers of systemic inflammation through the Diet Inflammatory Index (DII), but this association has not been studied in persons living with HIV (PLWH). Blood was collected from 28 INR PLWH with a blood CD4+ T cell count <350/µL despite ≥2 years of effective ART. Participants completed a Canadian Diet History Questionnaire, and their responses were used to calculate the DII. Plasma inflammatory markers (IFNγ, TNF, IL-6, sVCAM, D-dimer, sCD14 and CRP) were assayed by ELISA, cellular immune activation (HLA-DR and CD38 on CD4+ and CD8+ T cells) was quantified using flow cytometry, and small bowel permeability assessed by calculation of the urine LacMan ratio after drinking a mix of lactulose and mannitol. Participants were a median age of 57 years, had been on effective ART for 15 years, and the median DII was -1.91 (range of -3.78 to +2.23). No correlation was observed between DII and plasma markers of inflammation, levels of T cell activation, gut permeability, or the biomarker of bacterial translocation sCD14. Self-reported alcohol intake, a potential confounder of the relationship between diet and inflammatory biomarkers, was also not associated with systemic inflammation or gut permeability. Our findings suggest that other mechanisms, rather than diet, are likely to be the major driver of systemic inflammation in INR individuals.

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.

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.

Exploring the impact of HIV infection and antiretroviral therapy on placenta morphology.

INTRODUCTION: Women living with HIV experience more adverse birth outcomes; the mechanisms are not fully understood. We examined placenta morphology and associations with birth outcomes in a Canadian cohort of women living with HIV (HIV+) on antiretroviral therapy (ART) from conception and HIV-uninfected (HIV-) women. METHODS: Term placentas from 94 women (40 HIV-, 54 HIV+) were studied. Trimmed placenta weight was collected. Placenta digital photos were used to compute morphometric parameters. Regression models investigated associations between log-transformed placenta parameters and birth outcomes. RESULTS: We observed a trend towards lower placenta weight and smaller placenta area in the HIV+ group, both of which were significantly associated with small for gestational age births. HIV+ serostatus was associated with 6-fold (95%CI 2-20) greater odds of having placenta area in the lowest quartile (<236 cm2). Cord marginality (distance from the edge) was significantly lower in the HIV+ group (p = 0.004), with 35% of placenta having an abnormal (marginal or velamentous) cord insertion vs. 12.5% in the HIV- group (p = 0.01). Velamentous cord insertion was seen in 13% of placentas in the HIV+ vs. 0% in HIV- group (p = 0.02). A significant correlation between cord marginality and placenta thickness was observed in the HIV- group, with a more marginal cord being associated with a thicker placenta. This correlation was not observed in the HIV+ group. HIV+ placentas exposed to protease inhibitors were significantly less circular compared to the HIV- group (p = 0.03). CONCLUSION: Our data suggest that HIV/ART exposure affects placenta morphology and is associated with higher rates of abnormal cord insertion.

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.

Protecting Frontline Health Care Workers from COVID-19 with Hydroxychloroquine Pre-exposure Prophylaxis: A structured summary of a study protocol for a randomised placebo-controlled multisite trial in Toronto, Canada.

OBJECTIVES: Primary Objective: To determine if pre-exposure prophylaxis (PrEP) with 400mg hydroxychloroquine (HCQ), taken orally once daily reduces microbiologically confirmed COVID-19 among front line health care workers at high risk for SARS-CoV-2 exposure. Secondary Objectives: To compare the following between study arms: adverse events; symptomatic COVID-19; duration of symptomatic COVID-19; days hospitalized attributed to COVID-19; respiratory failure attributable to COVID-19 requiring i) non-invasive ventilation or ii) intubation/mechanical ventilation; mortality attributed to COVID-19, number of days unable to work attributed to COVID-19, seroconversion (COVID-19 negative to COVID-19 positive over the study period); ability of participant plasma to neutralize SARS-CoV-2 virus in vitro; To describe short-term psychological distress associated with risk of COVID-19 exposure at 1, 60, 120 days of the study. To explore laboratory markers within participants with confirmed COVID-19: including circulating markers of host immune and endothelial activation in participant plasma and their correlation with disease severity and outcome TRIAL DESIGN: The HEROS study is a two-arm, parallel-group, individually randomized (1:1 allocation ratio), placebo controlled, participant and investigator-blinded, multi-site superiority trial of oral HCQ 400 mg taken once daily for 90 days as PrEP to prevent COVID-19 in health care workers at high risk of SARS-CoV-2 exposure. At 90 days, there is an open label extension wherein all participants are offered a one-month course of HCQ 400mg once daily for PrEP of COVID-19. PARTICIPANTS: Frontline HCWs aged 18 years of age or older, at high risk of SARS-CoV-2 exposure (including staff of emergency departments, intensive care units, intubation teams, COVID-wards, and staff deployed to Long Term Care facilities) of five academic hospitals in downtown Toronto, Canada. Exclusion criteria include: currently pregnant, planning to become pregnant during the study period, and/or breast feeding; known hypersensitivity/allergy to hydroxychloroquine or to 4-aminoquinoline compounds; current use of hydroxychloroquine; known prolonged QT syndrome and/or baseline resting ECG with QTc>450 ms and/or concomitant medications which simultaneously may prolong the QTc that cannot be temporarily suspended/replaced; known pre-existing retinopathy, G6PD deficiency, porphyria, liver disease including cirrhosis, encephalopathy, hepatitis or alcoholism, diabetes on oral hypoglycemics or insulin, or renal insufficiency/failure; disclosure of self-administered use of hydroxychloroquine or chloroquine within 12 weeks prior to study; confirmed symptomatic COVID-19 at time of enrollment. INTERVENTION AND COMPARATOR: Intervention: hydroxychloroquine, 400mg (2 tablets) orally per day. Comparator: placebo, two tablets visually identical to the intervention, orally per day MAIN OUTCOMES: The primary outcome is microbiologically confirmed COVID-19 (i.e. SARS-CoV-2 infection). This is a composite endpoint which includes positive results from any validated SARS-CoV-2 diagnostic assay including detection of viral RNA, and/or seroconversion. Participants will be assessed at baseline, and then undergo monthly follow-up at day 30, 60, and 90, 120. At each visit, participants will provide an oropharyngeal sample, blood sample, and will undergo electrocardiogram monitoring of the QTc interval. Secondary outcome measures include: adverse events; symptom duration of COVID-19; days of hospitalization attributed to COVID-19; respiratory failure requiring ventilator support attributed to COVID-19; mortality attributed to COVID-19; total days off work attributed to COVID-19; seropositivity (reactive serology by day 120); and short term psychological impact of exposure to SARS-CoV-2 at day 1, 60, 120 days using the K10, a validated measure of non-specific psychological distress. RANDOMISATION: Within each site, participants will be individually randomized to either the intervention arm with HCQ or the placebo arm using a fixed 1:1 allocation ratio using an interactive web-based response system to ensure concealment of allocation. Randomization schedules will be computer-generated and blocked using variable block sizes. BLINDING (MASKING): All participants, research coordinators, technicians, clinicians and investigators will be blinded to the participant allocation group. Numbers to be randomised (sample size) N=988, randomised into two groups of 494 patients. TRIAL STATUS: This summary describes protocol version No. 1.6, May 15, 2020. Recruitment is ongoing - started April 20, 2020 and anticipated end date is July 30, 2021 TRIAL REGISTRATION: ISRCTN.com Identifier: ISRCTN14326006, registered April 14, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

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.

Protocol for a pilot randomised controlled trial evaluating feasibility and acceptability of cognitive remediation group therapy compared with mutual aid group therapy for people ageing with HIV-associated neurocognitive disorder (HAND) in Toronto, Canada.

INTRODUCTION: HIV-associated neurocognitive disorder (HAND) may affect 30%-50% of people ageing with HIV. HAND may increase stress and anxiety, and impede coping. Psychosocial group therapy may ameliorate HAND's symptoms, yet the ideal intervention is unclear. This protocol outlines a pilot randomised controlled trial (RCT)-designed using community-based participatory research-to pilot cognitive remediation group therapy (CRGT) against an active comparator. METHODS AND ANALYSIS: This is a pilot, parallel design, two-arm RCT that will recruit participants diagnosed with the mild neurocognitive disorder form of HAND from a neurobehavioural research unit at a tertiary care hospital in Toronto, Canada. Eligibility criteria include age ≥40 years, known HIV status for 5+ years, English fluency, able to consent and able to attend 8 weeks of group therapy. Eligible participants will be randomised to one of two treatment arms, each consisting of eight-session group interventions delivered once weekly at 3 hours per session. Arm 1 (novel) is CRGT, combining mindfulness-based stress reduction with brain training activities. Arm 2 (active control) is mutual aid group therapy. The primary outcomes are feasibility, measured by proportions of recruitment and completion, and acceptability, determined by a satisfaction questionnaire. The secondary outcome is intervention fidelity, where content analysis will be used to assess facilitator session reports. A between-group analysis will be conducted on exploratory outcomes of stress, anxiety, coping and use of intervention activities that will be collected at three time points. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Research Ethics Boards of St. Michael's Hospital and the University of Toronto. Findings will be disseminated through peer-reviewed publications, conference presentations and community reporting. This study could provide insight into design (eg, recruitment, measures) and intervention considerations (eg, structure, content) for a larger trial to lessen the burden of cognitive decline among people ageing with HIV. TRIAL REGISTRATION NUMBER: NCT03483740; Pre-results.