Healthcare utilisation and costs associated with adherence to antipsychotics among people living with HIV/AIDS and schizophrenia: a population-based cohort study in British Columbia, Canada.

OBJECTIVES: Non-adherence to antipsychotics is the greatest obstacle to treating schizophrenia. We assessed the economic and clinical impacts of adherence to antipsychotics among people living with HIV/AIDS (PLWH) and schizophrenia in British Columbia, Canada. DESIGN AND SETTING: A population-based cohort study in British Columbia, Canada. METHODS: Eligible PLWH were enrolled in the Seek and Treat for Optimal Prevention HIV/AIDS population-based cohort during 2001-2016, diagnosed with schizophrenia, on antipsychotics for ≥1 day, and followed for ≥1 year from schizophrenia diagnosis date or 1 January 2001, whichever occurred last. PRIMARY AND SECONDARY OUTCOME MEASURES: A two-part model assessed the marginal effect of adherence on healthcare costs (in 2016 Canadian dollar), while logistic regression examined the effect on virological failure, and generalised linear mixed models examined the effect on hospital readmissions within 30 days and length of hospital stay. RESULTS: Among 726 PLWH with schizophrenia, ≥80% adherence to antipsychotics increased from 25% (50/198) in 2001 to 41% (225/554) in 2016. In most years, we observed no difference in adherence to antipsychotics among those who used only injectables, only non-injectables, and a combination of both, or among those who have ever consumed typical/first-generation antipsychotics and who consumed only atypical/second-generation antipsychotics. Overall healthcare costs were higher in the non-adherent group ($C2185), driven by the average annual hospitalisation costs ($C5517), particularly among women ($C8806) and people who ever injected drugs (PWID) ($C5985). Non-adherent individuals also experienced higher hospital readmissions (adjusted odds ratio (aOR) 1.48, 95% CI 1.23 to 1.77), and longer hospital stays (adjusted mean ratio 1.23, 95% CI 1.13 to 1.35) in comparison to adherent individuals. We found no difference in virological failure by adherence groups, except when we stratified by gender where the aOR for women was 2.48 (95% CI 1.06 to 5.82). CONCLUSIONS: Our results showed that implementing strategies and interventions to increase antipsychotic adherence, particularly among women and PWID, will be critical in addressing this public health challenge.

Sexual minority status modifies the association between HIV risk behavior and prevalent mood or anxiety disorders in British Columbia, Canada.

PURPOSE: This study aimed at determining to what extent sexual minority status modifies the association between HIV risk behavior and prevalent mood or anxiety disorder diagnosis in British Columbia (BC), Canada, using a population-based survey. METHODS: This analysis was based on the cross-sectional 2013-2014 Canadian Community Health Survey. The sample was restricted to respondents in BC with valid responses to the survey items considered. A multivariable logistic model, where the behavioral HIV risk score exposure was nested into the sexual minority status modifier, estimated the odds of having a prevalent mood or an anxiety disorder. The behavioral HIV risk score (0, 1, 2, ≥ 3) included the following five measures: (1) age at first intercourse < 14 years, (2) condom use during last intercourse, (3) history of sexually transmitted infections, (5) number of sexual partners in the past 12 months (< 4, ≥ 4), and substance use in the past 12 months. RESULTS: Of the weighted sample (2,521,252), 97% (95% confidence interval (CI) 97-98) were heterosexual, while 3% (95% CI 2-3) were lesbian, gay, and bisexual (LGB). The prevalence of a mood or anxiety disorder diagnosis was 12% (95% CI 11-13). For every 1-level increment in the behavioral HIV risk score, the adjusted odds ratio of having a prevalent mood or anxiety disorder diagnosis was 1.29 (95% CI 1.03-1.54) for heterosexual respondents and 2.37 (95% CI 1.84-2.90) for LGB respondents. CONCLUSION: Sexual minority status modified the relationship between HIV risk behavior and prevalent mood or anxiety disorders, with a stronger association among LGB respondents. Healthcare providers should prioritize integrated care that addresses the intersectionality between sexual risk, substance use, and mood or anxiety disorders.

SARS-CoV-2 transmission in kindergarten to grade 12 schools in the Vancouver Coastal Health region: a descriptive epidemiologic study.

BACKGROUND: There is an urgent need to assess the role of schools in the spread of SARS-CoV-2 in Canada to inform public health measures. We describe the epidemiology of SARS-CoV-2 infection among students and staff in the Vancouver Coastal Health (VCH) region in the first 3 months of the 2020/2021 academic year, and examine the extent of transmission in schools. METHODS: This descriptive epidemiologic study using contact tracing data included individuals aged 5 years and older with SARS-CoV-2 infection, reported between Sept. 10 and Dec. 18, 2020, who worked in or attended kindergarten to grade 12 (K-12) schools in person in the VCH region. We described case and cluster characteristics and reported the number of school-based transmissions. RESULTS: During the study period, 699 cases of SARS-CoV-2 infection were reported (55 cases per 10 000 VCH school population). Among cases in VCH resident staff and students, 52.5% (354/674) were linked to a household case or cluster; less than 1.5% (< 10) of infected individuals were hospitalized and none died. Out of 699 cases present at school, 26 clusters with school-based transmission resulted in 55 secondary cases. Staff members accounted for 53.8% of index cases (14/26) while making up 14.3% of the school population (17 742/123 647). Among clusters, 88.5% (23) had fewer than 4 secondary cases. INTERPRETATION: In our population during the study period, there were no deaths and severe disease was rare; furthermore, school-based SARS-CoV-2 transmissions were uncommon and clusters were small. Our results, which relate primarily to symptomatic disease, support the growing body of evidence that schools likely did not play a major role in SARS-CoV-2 spread in 2020.

Overdose mortality is reducing the gains in life expectancy of antiretroviral-treated people living with HIV in British Columbia, Canada.

BACKGROUND: A remarkable reduction in AIDS-related mortality has been achieved through the widespread use of triple combination antiretroviral therapy, considerably increasing the life expectancy of people living with HIV (PLWH). However, these survival gains are now at risk in North America due to an unprecedented public health emergency: the deadly drug overdose epidemic. Drug overdoses are now the leading cause of unintentional death in British Columbia (BC), Canada and the United States due to synthetic opioids (e.g., fentanyl) in illegal markets. This manuscript aimed to estimate the effect of overdose mortality on life expectancy and identify covariates associated with the hazard for overdose mortality in the presence of competing risk among PLWH in BC. METHODS: Those eligible were aged ≥20 years, initiated antiretroviral therapy from 1-Apr-1996 to 30-Dec-2017, and were followed until 31-Dec-2017, last contact or death date. We estimated the potential gains in life expectancy from abridged life tables. We modelled the association between covariates and the cause-specific hazard for overdose mortality, accounting for mortality of other causes as a competing risk. RESULTS: Among the 10,362 PLWH, 3% experienced overdose mortality. The life expectancy at age 20 increased by 8.7 years from 2002-2007 to 2008-2013 compared to only 3.0 years from 2008-2013 to 2014-2017. The potential gain in life expectancy was 3.3 years at age 20 during the ongoing overdose epidemic (2014-2017). There were gender differences in life expectancies throughout the study period. People who have ever injected drugs, women and viral load monitoring non-compliance were key covariates associated with an increased hazard of overdose mortality. CONCLUSION: Survival gains among PLWH have been considerably reduced due to the ongoing overdose epidemic.

Excess burden of age-associated comorbidities among people living with HIV in British Columbia, Canada: a population-based cohort study.

OBJECTIVES: As people living with HIV (PLWH) live longer, morbidity and mortality from non-AIDS comorbidities have emerged as major concerns. Our objective was to compare prevalence trends and age at diagnosis of nine chronic age-associated comorbidities between individuals living with and without HIV. DESIGN AND SETTING: This population-based cohort study used longitudinal cohort data from all diagnosed antiretroviral-treated PLWH and 1:4 age-sex-matched HIV-negative individuals in British Columbia, Canada. PARTICIPANTS: The study included 8031 antiretroviral-treated PLWH and 32 124 HIV-negative controls (median age 40 years, 82% men). Eligible participants were ≥19 years old and followed for ≥1 year during 2000 to 2012. PRIMARY AND SECONDARY OUTCOME MEASURES: The presence of non-AIDS-defining cancers, diabetes, osteoarthritis, hypertension, Alzheimer's and/or non-HIV-related dementia, cardiovascular, kidney, liver and lung diseases were identified from provincial administrative databases. Beta regression assessed annual age-sex-standardised prevalence trends and Kruskal-Wallis tests compared the age at diagnosis of comorbidities stratified by rate of healthcare encounters. RESULTS: Across study period, the prevalence of all chronic age-associated comorbidities, except hypertension, were higher among PLWH compared with their community-based HIV-negative counterparts; as much as 10 times higher for liver diseases (25.3% vs 2.1%, p value<0.0001). On stratification by healthcare encounter rates, PLWH experienced most chronic age-associated significantly earlier than HIV-negative controls, as early as 21 years earlier for Alzheimer's and/or dementia. CONCLUSIONS: PLWH experienced higher prevalence and earlier age at diagnosis of non-AIDS comorbidities than their HIV-negative controls. These results stress the need for optimised screening for comorbidities at earlier ages among PLWH, and a comprehensive HIV care model that integrates prevention and treatment of chronic age-associated conditions. Additionally, the robust methodology developed in this study, which addresses concerns on the use of administrative health data to measure prevalence and incidence, is reproducible to other settings.

The syndemic effect of HIV/HCV co-infection and mental health disorders on acute care hospitalization rate among people living with HIV/AIDS: a population-based retrospective cohort study.

OBJECTIVE: Our primary objective was to examine the syndemic effect of HIV/HCV co-infection and mental health disorders (MHD) on the acute care hospitalization rate among people living with HIV (PLW-HIV) in British Columbia, Canada. Secondarily, we aimed to characterize the longitudinal trends in the aforementioned rate, while controlling for the effect of several factors. METHODS: In this retrospective cohort study, individuals were antiretroviral therapy-naïve, ≥ 18 years old, initiated treatment between 1 January 2000 and 31 December 2014, and were followed for at least 6 months until 31 December 2015 or last contact. The outcome was acute care hospitalization rate (every 6-month interval) per individual. The exposure was the interaction between HIV/HCV co-infection and MHD. Generalized non-linear mixed-effects models were built. RESULTS: Of the 4046 individuals in the final analytical sample, 1597 (39%) were PLW-HIV without MHD, 606 (15%) were people living with HIV and HCV (PLW-HIV/HCV) without MHD, 988 (24%) were PLW-HIV with MHD, and 855 (21%) were PLW-HIV/HCV with MHD. The adjusted rate ratios for acute care hospitalizations were 1.31 (95% [confidence interval] 1.13-1.52), 2.01 (95% CI 1.71-2.36), and 2.53 (95% CI 2.20-2.92) for PLW-HIV with MHD, PLW-HIV/HCV without MHD, and PLW-HIV/HCV with MHD, respectively, relative to PLW-HIV without MHD. CONCLUSION: The HIV/HCV co-infection and MHD interaction demonstrated a significant effect on the rate of acute care hospitalization, particularly for PLW-HIV/HCV with MHD. Implementing widely accessible integrative care model best practices may address this public health challenge.

Missed opportunities for earlier diagnosis of HIV in British Columbia, Canada: A retrospective cohort study.

BACKGROUND: Late HIV diagnosis is associated with increased AIDS-related morbidity and mortality as well as an increased risk of HIV transmission. In this study, we quantified and characterized missed opportunities for earlier HIV diagnosis in British Columbia (BC), Canada. DESIGN: Retrospective cohort. METHODS: A missed opportunity was defined as a healthcare encounter due to a clinical manifestation which may be caused by HIV infection, or is frequently present among those with HIV infection, but no HIV diagnosis followed within 30 days. We developed an algorithm to identify missed opportunities within one, three, and five years prior to diagnosis. The algorithm was applied to the BC STOP HIV/AIDS population-based cohort. Eligible individuals were ≥18 years old, and diagnosed from 2001-2014. Multivariable logistic regression identified factors associated with missed opportunities. RESULTS: Of 2119 individuals, 7%, 12% and 14% had ≥1 missed opportunity during one, three and five years prior to HIV diagnosis, respectively. In all analyses, individuals aged ≥40 years, heterosexuals or people who ever injected drugs, and those residing in Northern health authority had increased odds of experiencing ≥1 missed opportunity. In the three and five-year analysis, individuals with a CD4 count <350 cells/mm3 were at higher odds of experiencing ≥1 missed opportunity. Prominent missed opportunities were related to recurrent pneumonia, herpes zoster/shingles among younger individuals, and anemia related to nutritional deficiencies or unspecified cause. CONCLUSIONS: Based on our newly-developed algorithm, this study demonstrated that HIV-diagnosed individuals in BC have experienced several missed opportunities for earlier diagnosis. Specific clinical indicator conditions and population sub-groups at increased risk of experiencing these missed opportunities were identified. Further work is required in order to validate the utility of this proposed algorithm by establishing the sensitivity, specificity, positive and negative predictive values corresponding to the incidence of the clinical indicator conditions among both HIV-diagnosed and HIV-negative populations.

The impact of HCV co-infection status on healthcare-related utilization among people living with HIV in British Columbia, Canada: a retrospective cohort study.

BACKGROUND: The burden of HCV among those living with HIV remains a major public health challenge. We aimed to characterize trends in healthcare-related visits (HRV) of people living with HIV (PLW-HIV) and those living with HIV and HCV (PLW-HIV/HCV), in British Columbia (BC), and to identify risk factors associated with the highest HRV rates over time. METHODS: Eligible individuals, recruited from the BC Seek and Treat for Optimal Prevention of HIV/AIDS population-based retrospective cohort (N = 3955), were ≥ 18 years old, first started combination antiretroviral therapy (ART) between 01/01/2000-31/12/2013, and were followed for ≥6 months until 31/12/2014. The main outcome was HRV rate. The main exposure was HIV/HCV co-infection status. We built a confounder non-linear mixed effects model, adjusting for several demographic and time-dependent factors. RESULTS: HRV rates have decreased since 2000 in both groups. The overall age-sex standardized HRV rate (per person-year) among PLW-HIV and PLW-HIV/HCV was 21.11 (95% CI 20.96-21.25) and 41.69 (95% CI 41.51-41.88), respectively. The excess in HRV in the co-infected group was associated with late presentation for ART, history of injection drug use, sub-optimal ART adherence and a higher number of comorbidities. The adjusted HRV rate ratio for PLW-HIV/HCV in comparison to PLW-HIV was 1.18 (95% CI 1.13-1.24). CONCLUSIONS: Although HRV rates have decreased over time in both groups, PLW-HIV/HCV had 18% higher HRV than those only living with HIV. Our results highlight several modifiable risk factors that could be targeted as potential means to minimize the disease burden of this population and of the healthcare system.

Progress towards the United Nations 90-90-90 and 95-95-95 targets: the experience in British Columbia, Canada.

INTRODUCTION: Antiretroviral therapy (ART) scale-up is central to the global strategy to control the HIV/AIDS pandemic. To accelerate efforts towards ending the AIDS epidemic, the Joint United Nations Programme on HIV/AIDS released the 90-90-90 and 95-95-95 targets, which have recently been approved by the United Nations (UN). This study characterizes the province of British Columbia (BC)'s progress towards achieving the UN targets, predicts a trajectory up to 2030 according to each of the individual steps (i.e. %Diagnosed, %On ART and %Virologically Suppressed), and identifies the population sub-groups at higher risk of not achieving these targets. METHODS: The analyses were based on linked individual-level datasets of people living with HIV (PLWH) in BC, aged ≥18 months, from 2000 to 2013. Using past trends in HIV prevalence and of each individual UN targets, we forecasted these outcomes until 2030 via generalized additive models. We ran a second set of analyses to assess the associations between individual demographic and behavioural factors and each of the individual steps of the UN targets. Lastly, we performed sensitivity analyses to account for uncertainty associated with prevalence estimates and suppression definitions. RESULTS: Among the estimated 10666 PLWH in BC in 2013, 82% were diagnosed, 76% of those diagnosed were on ART and 83% of those on ART were virologically suppressed. We identified that females, PLWH aged <30 years and those with unknown risk or who self-identify as having a history of injection drug use were the population subgroups that experienced the most challenge in engaging on ART and achieving viral suppression. Our model projections suggest that BC will achieve 90%-91%-90% and 97%-99%-97% by 2020 and 2030 respectively. CONCLUSIONS: As we approach 2020, BC is rapidly moving towards achieving the UN targets. However, region-specific challenges persist. Identification of remaining regional challenges will be essential to achieving the proposed UN targets and therefore fulfilling the promise to end AIDS as a pandemic by 2030.

Oncolytic virus synergizes with Smac mimetic compounds to induce rhabdomyosarcoma cell death in a syngeneic murine model.

Rhabdomyosarcoma (RMS), a neoplasm characterized by undifferentiated myoblasts, is the most common soft tissue tumour in children. Therapeutic resistance is common in RMS and is often caused by acquired defects in the cellular apoptotic program. Smac mimetic compounds (SMCs) are a novel class of inhibitor of apoptosis (IAP) antagonists that are currently under clinical development as cancer therapeutics. We previously reported that cIAP1 is overexpressed in human primary RMS tumours and in patient-derived RMS cell lines where it drives resistance to apoptosis. In this study, we investigated whether inflammatory cytokine production triggered by activators of innate immunity synergizes with LCL161 to induce bystander killing of RMS cells in vitro and in vivo. Indeed, we show that innate immune stimuli (oncolytic virus (VSVΔ51-GFP), interferon γ (IFNγ), and tumour necrosis factor-like weak inducer of apoptosis (TWEAK)) combine with SMCs in vitro to reduce cell viability in the Kym-1 RMS cancer cell line. Other human RMS cell lines (RH36, RH41, RD, RH18, RH28, and RH30) and the murine RMS cell line 76-9 are resistant to treatment with LCL161 alone or in combination with immune stimulants in in vitro cell viability assays. In contrast, we report that the combination of LCL161 and VSVΔ51-GFP reduces tumour volume and prolongs survival in a 76-9 syngeneic murine model. Our results support further exploration of the combined use of IAP antagonists and innate immune stimuli as a therapeutic approach for RMS cancers.