DNA Methylation Demonstrates Bronchoalveolar Cell Senescence in People Living with HIV: An Observational Cohort Study.

BACKGROUND: DNA methylation may be a link between HIV, aging, and the increased risk of lung comorbidities. We investigated whether bronchoalveolar lavage (BAL) cells of people living with HIV (PLWH) demonstrate epigenetic disruptions and advanced epigenetic aging. METHODS: BAL cell DNA methylation from 25 PLWH and 16 HIV-uninfected individuals were tested for differential methylation of Alu and LINE-1 sites, markers of aging. We used a weighted gene correlation network analysis to identify HIV- and age-associated co-methylation networks. We tested the effect of HIV on DNA methylation using a robust linear model (false discovery rate < 0.10). RESULTS: The BAL cells of PLWH were marked by global hypomethylation in both Alu and LINE-1 elements. Six co-methylated CpG networks were identified that were significantly associated with age; of these, the red module was significantly differentially methylated in PLWH and enriched pathways (e.g., Ras signaling and T-cell receptors). We identified 6428 CpG sites associated with HIV. CONCLUSIONS: We have shown here for the first time that alterations in the DNA methylation of BAL cells in the lung with HIV show a pattern of advanced aging. This study strongly supports that HIV may contribute to an increased the risk of lung comorbidities through the epigenetics of aging.

Non-AIDS-defining comorbidities impact health related quality of life among older adults living with HIV.

Introduction: The life expectancy of people living with HIV receiving effective combination antiretroviral therapy is approaching that of the general population and non AIDS-defining age-related comorbidities are becoming of greater concern. In order to support healthy aging of this population, we set out to explore the association between multimorbidity (defined as presence of 2 or more non AIDS-defining comorbidities) and quality of life (QoL). Methods: We performed a cross-sectional analysis using data from the Correlates of Healthy Aging in Geriatric HIV (CHANGE HIV) study, a Canadian cohort of people living with HIV age 65 years and older. Study participants completed two QoL modules, the general QoL and health related QoL (HR-QoL). Results: 433 participants were included in the analysis with a median age of 69 years (interquartile range, IQR 67-72). The median number of comorbidities among study participants was 3 (IQR 2-4), with 78% meeting the definition of multimorbidity. General QoL scores (median 66, IQR 58-76) were lower than HR-QoL scores (median 71, IQR 61-83) and were not associated with multimorbidity after adjusting for age, sex, relationship status, household income, exercise, tobacco smoking history, malnutrition, time since HIV diagnosis, and HIV-related stigma. In contrast, multimorbidity was associated with lower HR-QoL (adjusted ß = -4.57, 95% CI -8.86, -0.28) after accounting for the same variables. Several social vulnerabilities (not having a partner, low household income), health behaviours (lower engagement in exercise, smoking), and HIV-related factors (HIV stigma, longer time since HIV diagnosis) were also associated with lower QoL. Discussion: Overall, our study demonstrated a high burden of multimorbidity among older adults living with HIV in Canada, which has a negative impact on HR-QoL. Interventions aimed at preventing and managing non-AIDS-defining comorbidities should be assessed in people living with HIV to determine whether this can improve their HR-QoL.

Microbial dysbiosis and the host airway epithelial response: insights into HIV-associated COPD using multi'omics profiling.

BACKGROUND: People living with HIV (PLWH) are at increased risk of developing Chronic Obstructive Pulmonary Disease (COPD) independent of cigarette smoking. We hypothesized that dysbiosis in PLWH is associated with epigenetic and transcriptomic disruptions in the airway epithelium. METHODS: Airway epithelial brushings were collected from 18 COPD + HIV + , 16 COPD - HIV + , 22 COPD + HIV - and 20 COPD - HIV - subjects. The microbiome, methylome, and transcriptome were profiled using 16S sequencing, Illumina Infinium Methylation EPIC chip, and RNA sequencing, respectively. Multi 'omic integration was performed using Data Integration Analysis for Biomarker discovery using Latent cOmponents. A correlation > 0.7 was used to identify key interactions between the 'omes. RESULTS: The COPD + HIV -, COPD -HIV + , and COPD + HIV + groups had reduced Shannon Diversity (p = 0.004, p = 0.023, and p = 5.5e-06, respectively) compared to individuals with neither COPD nor HIV, with the COPD + HIV + group demonstrating the most reduced diversity. Microbial communities were significantly different between the four groups (p = 0.001). Multi 'omic integration identified correlations between Bacteroidetes Prevotella, genes FUZ, FASTKD3, and ACVR1B, and epigenetic features CpG-FUZ and CpG-PHLDB3. CONCLUSION: PLWH with COPD manifest decreased diversity and altered microbial communities in their airway epithelial microbiome. The reduction in Prevotella in this group was linked with epigenetic and transcriptomic disruptions in host genes including FUZ, FASTKD3, and ACVR1B.

Identifying Longitudinal CD4:CD8 Ratio Trajectories Indicative of Chronic Renal Disease Risk among People Living with HIV: An Application of Growth Mixture Models.

The incidence of chronic kidney disease (CKD) is increasing among people living with HIV (PLWH). Routine monitoring of indicators such as CD4:CD8 ratio might improve the early detection of CKD. Our objective was to identify clinically relevant CD4:CD8 ratio trajectories indicative of CKD risk. Participants were ≥ 18 years old, initiated antiretroviral therapy between 2000 and 2016, and were followed for ≥6 months until 31 March 2017 or last contact date. Outcome was incidence of CKD. Growth mixture models (GMMs) and decay models were used to compare CD4:CD8 ratio trajectories. Following GMM, 4547 (93.5%) participants were classified in Class 1 with 5.4% developing CKD, and 316 (6.5%) participants were classified in Class 2 with 20.9% developing CKD. The final model suggested that participants in Class 2 had 8.72 times the incidence rate of developing CKD than those in Class 1. Exponential decay models indicated a significant CD4:CD8 ratio decline among Class 2 participants who developed CKD. Among those who developed CKD in Class 2, starting at 5.5 years of follow-up, the slope of their ratio trajectory curve changed significantly, and the rate of decline increased dramatically. Routine monitored CD4:CD8 ratios can be an effective strategy to identify early CKD risk among PLWH.

Correlates of Healthy Aging in Geriatric HIV (CHANGE HIV)-CTN 314.

The Correlates of Healthy Aging in Geriatric HIV (CHANGE HIV) study, CTN 314, is the first Canadian cohort of people living with HIV aged 65 years and older. The cohort was established with the purpose of characterizing the multidimensional health status of this population and identifying factors influencing healthy aging. The study builds on the World Health Organization (WHO) Aging and Health conceptual framework, generating a comprehensive profile of health domains (physical, social, mental health, cognitive function, and quality of life), health determinants (biologic, personal, and environmental), and HIV-specific factors that may interact with and influence health in people aging with HIV. The data for the first 353 participants are presented, focusing on sociodemographic factors, comorbidities, coinfections, frailty, cognitive function, loneliness, and resilience using a sex/gender stratified analysis. The cohort thus far is 91% men and the median age is 70 years (range from 65 to 85). Several vulnerabilities were observed, including a high prevalence of comorbidities and frailty. Women especially faced financial insecurity and precarious social structures; a large proportion live alone and only 6% are married or in steady relationships. Identifying strategies to address these vulnerabilities will empower people aging with HIV to optimize their health, quality of life, and independence.

People With Human Immunodeficiency Virus Receiving Suppressive Antiretroviral Therapy Show Typical Antibody Durability After Dual Coronavirus Disease 2019 Vaccination and Strong Third Dose Responses.

BACKGROUND: Longer-term humoral responses to 2-dose coronavirus disease 2019 (COVID-19) vaccines remain incompletely characterized in people living with human immunodeficiency virus (HIV) (PLWH), as do initial responses to a third dose. METHODS: We measured antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain, angiotensin-converting enzyme 2 (ACE2) displacement, and viral neutralization against wild-type and Omicron strains up to 6 months after 2-dose vaccination, and 1 month after the third dose, in 99 PLWH receiving suppressive antiretroviral therapy and 152 controls. RESULTS: Although humoral responses naturally decline after 2-dose vaccination, we found no evidence of lower antibody concentrations or faster rates of antibody decline in PLWH compared with controls after accounting for sociodemographic, health, and vaccine-related factors. We also found no evidence of poorer viral neutralization in PLWH after 2 doses, nor evidence that a low nadir CD4+ T-cell count compromised responses. Post-third-dose humoral responses substantially exceeded post-second-dose levels, though Omicron-specific responses were consistently weaker than responses against wild-type virus. Nevertheless, post-third-dose responses in PLWH were comparable to or higher than controls. An mRNA-1273 third dose was the strongest consistent correlate of higher post-third-dose responses. CONCLUSION: PLWH receiving suppressive antiretroviral therapy mount strong antibody responses after 2- and 3-dose COVID-19 vaccination. Results underscore the immune benefits of third doses in light of Omicron.

Antibody response durability following three-dose coronavirus disease 2019 vaccination in people with HIV receiving suppressive antiretroviral therapy.

BACKGROUND: Limited data exist regarding longer term antibody responses following three-dose coronavirus disease 2019 (COVID-19) vaccination, and the impact of a first SARS-CoV-2 infection during this time, in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART). We quantified wild-type-specific, Omicron BA.1-specific and Omicron BA.5-specific responses up to 6 months post-third dose in 64 PWH and 117 controls who remained COVID-19-naive or experienced their first SARS-CoV-2 infection during this time. DESIGN: Longitudinal observational cohort. METHODS: We quantified wild-type-specific and Omicron-specific anti-Spike receptor-binding domain IgG concentrations, ACE2 displacement activities and live virus neutralization at 1, 3 and 6 months post-third vaccine dose. RESULTS: Third doses boosted all antibody measures above two-dose levels, but BA.1-specific responses remained significantly lower than wild-type-specific ones, with BA.5-specific responses lower still. Serum IgG concentrations declined at similar rates in COVID-19-naive PWH and controls post-third dose (median wild-type-specific and BA.1-specific half-lives were between 66 and 74 days for both groups). Antibody function also declined significantly yet comparably between groups: 6 months post-third dose, BA.1-specific neutralization was undetectable in more than 80% of COVID-19 naive PWH and more than 90% of controls. Breakthrough SARS-CoV-2 infection boosted antibody concentrations and function significantly above vaccine-induced levels in both PWH and controls, though BA.5-specific neutralization remained significantly poorer than BA.1 even post-breakthrough. CONCLUSION: Following three-dose COVID-19 vaccination, antibody response durability in PWH receiving ART is comparable with controls. PWH also mounted strong responses to breakthrough infection. Due to temporal response declines, however, COVID-19-naive individuals, regardless of HIV status, would benefit from a fourth dose within 6 months of their third.

The relationship between the epigenetic aging biomarker "grimage" and lung function in both the airway and blood of people living with HIV: An observational cohort study.

BACKGROUND: Age-related comorbidities such as chronic obstructive pulmonary disease (COPD) are common in people living with human immunodeficiency virus (PLWH). We investigated the relationship between COPD and the epigenetic age of the airway epithelium and peripheral blood of PLWH. METHODS: Airway epithelial brushings from 34 PLWH enrolled in the St. Paul's Hospital HIV Bronchoscopy cohort and peripheral blood from 378 PLWH enrolled in The Strategic Timing of Antiretroviral Treatment (START) study were profiled for DNA methylation. The DNA methylation biomarker of age and healthspan, GrimAge, was calculated in both tissue compartments. We tested the association of GrimAge with COPD in the airway epithelium and airflow obstruction as defined by an FEV1/FVC<0.70, and FEV1 decline over 6 years in blood. FINDINGS: The airway epithelium of PLWH with COPD was associated with greater GrimAge residuals compared to PLWH without COPD (Beta=3.18, 95%CI=1.06-5.31, P=0.005). In blood, FEV1/FVC

Airway Aging and Methylation Disruptions in HIV-associated Chronic Obstructive Pulmonary Disease.

Rationale: Age-related diseases like chronic obstructive pulmonary disease (COPD) occur at higher rates in people living with human immunodeficiency virus (PLWH) than in uninfected populations. Objectives: To identify whether accelerated aging can be observed in the airways of PLWH with COPD, manifest by a unique DNA methylation signature. Methods: Bronchial epithelial brushings from PLWH with and without COPD and HIV-uninfected adults with and without COPD (N = 76) were profiled for DNA methylation and gene expression. We evaluated global Alu and LINE-1 methylation and calculated the epigenetic age using the Horvath clock and the methylation telomere length estimator. To identify genome-wide differential DNA methylation and gene expression associated with HIV and COPD, robust linear models were used followed by an expression quantitative trait methylation (eQTM) analysis. Measurements and Main Results: Epigenetic age acceleration and shorter methylation estimates of telomere length were found in PLWH with COPD compared with PLWH without COPD and uninfected patients with and without COPD. Global hypomethylation was identified in PLWH. We identified 7,970 cytosine bases located next to a guanine base (CpG sites), 293 genes, and 9 expression quantitative trait methylation-gene pairs associated with the interaction between HIV and COPD. Actin binding LIM protein family member 3 (ABLIM3) was one of the novel candidate genes for HIV-associated COPD highlighted by our analysis. Conclusions: Methylation age acceleration is observed in the airway epithelium of PLWH with COPD, a process that may be responsible for the heightened risk of COPD in this population. Their distinct methylation profile, differing from that observed in patients with COPD alone, suggests a unique pathogenesis to HIV-associated COPD. The associations warrant further investigation to establish causality.

Humoral immune responses to COVID-19 vaccination in people living with HIV receiving suppressive antiretroviral therapy.

Humoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely characterized. We measured circulating antibodies against the SARS-CoV-2 spike protein receptor-binding domain (RBD), ACE2 displacement and viral neutralization activities one month following the first and second COVID-19 vaccine doses, and again 3 months following the second dose, in 100 adult PLWH and 152 controls. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525-935) cells/mm3, though nadir CD4+ T-cell counts ranged as low as <10 cells/mm3. After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was associated with lower anti-RBD antibody concentrations and ACE2 displacement activity after one vaccine dose. Following two doses however, HIV was not significantly associated with the magnitude of any humoral response after multivariable adjustment. Rather, older age, a higher burden of chronic health conditions, and dual ChAdOx1 vaccination were associated with lower responses after two vaccine doses. No significant correlation was observed between recent or nadir CD4+ T-cell counts and responses to two vaccine doses in PLWH. These results indicate that PLWH with well-controlled viral loads and CD4+ T-cell counts in a healthy range generally mount strong initial humoral responses to dual COVID-19 vaccination. Factors including age, co-morbidities, vaccine brand, response durability and the rise of new SARS-CoV-2 variants will influence when PLWH will benefit from additional doses. Further studies of PLWH who are not receiving antiretroviral treatment or who have low CD4+ T-cell counts are needed, as are longer-term assessments of response durability.

People with HIV receiving suppressive antiretroviral therapy show typical antibody durability after dual COVID-19 vaccination, and strong third dose responses.

Background: Longer-term humoral responses to two-dose COVID-19 vaccines remain incompletely characterized in people living with HIV (PLWH), as do initial responses to a third dose. Methods: We measured antibodies against the SARS-CoV-2 spike protein receptor-binding domain, ACE2 displacement and viral neutralization against wild-type and Omicron strains up to six months following two-dose vaccination, and one month following the third dose, in 99 PLWH receiving suppressive antiretroviral therapy, and 152 controls. Results: Though humoral responses naturally decline following two-dose vaccination, we found no evidence of lower antibody concentrations nor faster rates of antibody decline in PLWH compared to controls after accounting for sociodemographic, health and vaccine-related factors. We also found no evidence of poorer viral neutralization in PLWH after two doses, nor evidence that a low nadir CD4+ T-cell count compromised responses. Post-third-dose humoral responses substantially exceeded post-second-dose levels, though anti-Omicron responses were consistently weaker than against wild-type.Nevertheless, post-third-dose responses in PLWH were comparable to or higher than controls. An mRNA-1273 third dose was the strongest consistent correlate of higher post-third-dose responses. Conclusion: PLWH receiving suppressive antiretroviral therapy mount strong antibody responses after two- and three-dose COVID-19 vaccination. Results underscore the immune benefits of third doses in light of Omicron.

Improving Post-Release Care Engagement for People Living with HIV Involved in the Criminal Justice System: A Systematic Review.

Given sub-optimal HIV care outcomes for people living with HIV (PLWH) post-release from incarceration, we systematically searched peer-reviewed literature (2010-2021) describing controlled trial interventions aimed at improving Antiretroviral Therapy (ART) adherence and care linkage following release from correctional facilities for PLWH. Of 392 studies, 16 (4%) met the inclusion criteria. All studies were conducted in the United States and involved some form of intensive case management. Trials that scored highest in terms of study quality provided cell phones for engagement, reported sustained viral load suppression as a measurable outcome to infer ART adherence, and measured longitudinal data collected for at least 3-to-6 months following release. The two trials that demonstrated improved HIV viral load suppression involved Peer Navigators, and incentivized undetectable viral load, respectively. Facilitating support for addictions and addressing other social and structural barriers to achieving optimal health is also of vital importance in bridging care gaps for PLWH.

RESUMEN: Debido a los resultados suboptimos en los cuidados de las personas que viven con VIH después de su liberación del encarcelamiento, nosotros realizamos una revisión sistemática de la literatura (2010­2021) que describe ensayos control de intervenciones para mejorar la adherencia a la terapia antiretrovirales (TAR) y el vinculo con la atención medica después de la liberación del encarcelamiento de las personas que viven con VIH. De los 392 estudios, 16 (4%) cumplieron con los criterios de inclusión. Todos los estudios fueron realizados en los Estados Unidos e incluyen alguna forma de cuidados con manejo intensivo. Los ensayos que tenían los puntajes mas altos en términos de calidad proveían teléfonos celulares para la vinculación, reportaban supresión de la carga viral sostenida como medida indirecta de adherencia al TAR, y han medido datos longitudinales por lo menos de tres a seis meses después de la liberación carcelaria. Los dos ensayos que demostraron mejora en la supresión de la carga viral del VIH involucraban a los pares navegadores e incentivaban la carga viral no detectable, respectivamente. Facilitando el soporte para la adicción y el entendimiento de otras barreras sociales y estructurales para alcanzar una salud optima, es de vital importancia para superar las brechas en la atención de las personas que viven con VIH.

Humoral immune responses to COVID-19 vaccination in people living with HIV receiving suppressive antiretroviral therapy.

Humoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely understood. We measured circulating antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, ACE2 displacement and live viral neutralization activities one month following the first and second COVID-19 vaccine doses in 100 adult PLWH and 152 controls. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525-935) cells/mm 3 . Nadir CD4+ T-cell counts ranged as low as <10 (median 280; IQR 120-490) cells/mm 3 . After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was significantly associated with 0.2 log 10 lower anti-RBD antibody concentrations (p=0.03) and ∻11% lower ACE2 displacement activity (p=0.02), but not lower viral neutralization (p=0.1) after one vaccine dose. Following two doses however, HIV was no longer significantly associated with the magnitude of any response measured. Rather, older age, a higher burden of chronic health conditions, and having received two ChAdOx1 doses (versus a heterologous or dual mRNA vaccine regimen) were independently associated with lower responses. After two vaccine doses, no significant correlation was observed between the most recent or nadir CD4+ T-cell counts and vaccine responses in PLWH. These results suggest that PLWH with well-controlled viral loads on antiretroviral therapy and CD4+ T-cell counts in a healthy range will generally not require a third COVID-19 vaccine dose as part of their initial immunization series, though other factors such as older age, co-morbidities, vaccine regimen type, and durability of vaccine responses will influence when this group may benefit from additional doses. Further studies of PLWH who are not receiving antiretroviral treatment and/or who have low CD4+ T-cell counts are needed.

Incidence of diabetes mellitus among people living with and without HIV in British Columbia, Canada between 2001 and 2013: a longitudinal population-based cohort study.

INTRODUCTION: People living with HIV (PLHIV) are increasingly at risk of age-related comorbidities such as diabetes mellitus (DM). While DM is associated with elevated mortality and morbidity, understanding of DM among PLHIV is limited. We assessed the incidence of DM among people living with and without HIV in British Columbia (BC), Canada, during 2001-2013. METHODS: We used longitudinal data from a population-based cohort study linking clinical data and administrative health data. We included PLHIV who were antiretroviral therapy (ART) naïve at baseline, and 1:5 age-sex-matched persons without HIV. All participants had ≥5 years of historic data pre-baseline and ≥1 year(s) of follow-up. DM was identified using the BC Ministry of Health's definitions applied to hospitalisation, physician billing and drug dispensation datasets. Incident DM was identified using a 5-year run-in period. In addition to unadjusted incidence rates (IRs), we estimated adjusted incidence rate ratios (IRR) using Poisson regression and assessed annual trends in DM IRs per 1000 person years (PYs) between 2001 and 2013. RESULTS: A total of 129 PLHIV and 636 individuals without HIV developed DM over 17 529 PYs and 88,672 PYs, respectively. The unadjusted IRs of DM per 1000 PYs were 7.4 (95% CI 6.2 to 8.8) among PLHIV and 7.2 (95% CI 6.6 to 7.8) for individuals without HIV. After adjustment for confounding, HIV serostatus was not associated with DM incidence (adjusted IRR: 1.03, 95% CI 0.83 to 1.27). DM incidence did not increase over time among PLHIV (Kendall trend test: p=0.9369), but it increased among persons without HIV between 2001 and 2013 (p=0.0136). CONCLUSIONS: After adjustment, HIV serostatus was not associated with incidence of DM, between 2001 and 2013. Future studies should investigate the impact of ART on mitigating the potential risk of DM among PLHIV.

The Impact of Treatment as Prevention on the HIV Epidemic in British Columbia, Canada.

PURPOSE OF REVIEW: This study proposes to describe the impact of a publicly funded Treatment as Prevention (TasP) strategy in British Columbia (BC), Canada, in decreasing the individual and public health impact of the HIV/AIDS Epidemic. RECENT FINDINGS: In BC, TasP has been associated with a steady decline in HIV-related morbidity and mortality. At the same time, a demographic transition was observed among people living with HIV (PLWH), with the majority of those on antiretroviral treatment (ART) now ≥ 50 years of age, living with at least one comorbidity, and dying from age-associated comorbidities. We also documented a progressive increase in the proportion of viral load suppression as a result of ART expansion. While the pre-ART CD4 T cell count has increased steadily in recent years, there is still a large proportion of PLWH being diagnosed in later stages of HIV infection. New HIV diagnoses have been rapidly declining, however to a lesser extent among men who have sex with men (MSM), and BC is currently experiencing an increase in infectious syphilis cases in this population. These facts reinforce the effectiveness of TasP in decreasing HIV transmission, but at the same time, it highlights the need for further innovation to enhance the control of HIV and syphilis among MSM. This study supports the development of new approaches that address existing gaps in the TasP strategy in BC, and the future health needs of PLWH.

The potential impact of initiating antiretroviral therapy with integrase inhibitors on HIV transmission risk in British Columbia, Canada.

BACKGROUND: Available agents within the integrase strand-transfer inhibitor (INSTI) class have been shown to lead to a faster decay in viral load than other regimens. Therefore, we estimated the potential reduction in HIV transmission risk among antiretroviral-naïve individuals initiating on INSTI-based antiretroviral therapy (ART), focusing on the gay, bisexual and other men who have sex with men (gbMSM) population and various degrees of sexual activity. METHODS: Using two mathematical models that estimate the HIV transmission risk corresponding to different viral loads, we estimated the average probability of HIV transmission per risky contact for gbMSM during the six months post-ART initiation, stratified by stage of HIV infection, viral load at ART initiation and type of first-line ART (i.e., INSTI or non-INSTI-based ART). This study focused individuals who initiated ART between 2011 and 2016 with at least one year of follow-up in British Columbia, Canada. FINDINGS: Time to first virologic suppression for INSTI-based regimens was 21.4 days (95% credible interval (CI) 19.9-23.2), compared to 58.6 days (95% CI 54.1-62.2) for non-INSTI regimens. We showed that INSTI-based regimens could reduce the HIV transmission risk by at least 25% among those with viral load ≥ 5 log10 copies/mL at ART initiation. INTERPRETATION: Initiating ART on INSTI-based regimens has the potential to reduce HIV transmission risk among individuals with high baseline viral load levels, especially among those with high levels of sexual activity. FUNDING: The British Columbia Ministry of Health, the Canadian Institutes of Health Research, and the Michael Smith Foundation for Health Research.

Risk of myocardial infarction among people living with HIV: an updated systematic review and meta-analysis.

OBJECTIVE: Cardiovascular disease (CVD) is one of the leading non-AIDS-defining causes of death among HIV-positive (HIV+) individuals. However, the evidence surrounding specific components of CVD risk remains inconclusive. We conducted a systematic review and meta-analysis to synthesise the available evidence and establish the risk of myocardial infarction (MI) among HIV+ compared with uninfected individuals. We also examined MI risk within subgroups of HIV+ individuals according to exposure to combination antiretroviral therapy (ART), ART class/regimen, CD4 cell count and plasma viral load (pVL) levels. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews until 18 July 2018. Furthermore, we scanned recent HIV conference abstracts (CROI, IAS/AIDS) and bibliographies of relevant articles. ELIGIBILITY CRITERIA: Original studies published after December 1999 and reporting comparative data relating to the rate of MI among HIV+ individuals were included. DATA EXTRACTION AND SYNTHESIS: Two reviewers working in duplicate, independently extracted data. Data were pooled using random-effects meta-analysis and reported as relative risk (RR) with 95% CI. RESULTS: Thirty-two of the 8130 identified records were included in the review. The pooled RR suggests that HIV+ individuals have a greater risk of MI compared with uninfected individuals (RR: 1.73; 95% CI 1.44 to 2.08). Depending on risk stratification, there was moderate variation according to ART uptake (RR, ART-treated=1.80; 95% CI 1.17 to 2.77; ART-untreated HIV+ individuals: 1.25; 95% CI 0.93 to 1.67, both relative to uninfected individuals). We found low CD4 count, high pVL and certain ART characteristics including cumulative ART exposure, any/cumulative use of protease inhibitors as a class, and exposure to specific ART drugs (eg, abacavir) to be importantly associated with a greater MI risk. CONCLUSIONS: Our results indicate that HIV infection, low CD4, high pVL, cumulative ART use in general including certain exposure to specific ART class/regimen are associated with increased risk of MI. The association with cumulative ART may be an index of the duration of HIV infection with its attendant inflammation, and not entirely the effect of cumulative exposure to ART per se. PROSPERO REGISTRATION NUMBER: CRD42014012977.

Retention in care and mortality trends among patients receiving comprehensive care for HIV infection: a retrospective cohort study.

BACKGROUND: Studies examining the relation between comprehensive care and health outcomes associated with comorbidities unrelated to HIV infection have focused mainly on the health outcomes of HIV-infected people and comorbid substance use disorders. We aimed to assess the impact of retention in comprehensive HIV infection care on overall, AIDS-related and non-AIDS-related mortality. METHODS: Using a retrospective cohort design, we collected data for HIV-infected patients aged 19 years or more who first visited a comprehensive HIV infection clinic in Vancouver between Jan. 1, 2004, and Dec. 31, 2014. We defined retention in care as visit constancy (whether the patient attended the clinic at least once per given period) of 75% or greater. We used Poisson regression modelling to examine mortality trends. We performed Cox proportional hazards modelling to assess survival by retention during the first year of follow-up and identify factors associated with death. RESULTS: A total of 2101 patients were included in the study. Of the 2101, 1340 (63.8%) were retained in the first year of care, and 271 (12.9%) died during the study period. Among the 264 cases in which the cause of death was known, although the primary underlying cause of death (74 [28.0%]) was AIDS-related, half of all AIDS-related deaths (37/74 [50%]) occurred early in the study (2004-2007). In later years, most deaths (147/184 [79.9%]) were non-AIDS-related. Overall mortality was significantly reduced among patients with higher retention in care during the first year of follow-up (per 20% increase in visit constancy; adjusted hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.79-0.96). Higher retention was also associated with reduced risk of AIDS-related death (adjusted HR 0.79, 95% CI 0.64-0.97). INTERPRETATION: Although there was an overall trend toward decreased AIDS-related mortality over time, retention in care markedly decreased the likelihood of death. Maintaining patient engagement in comprehensive ancillary care is a patient-centred way of decreasing mortality rates among HIV-infected people.

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.

Stroke and Systemic Thromboembolism Prevention in People Living With Human Immunodeficiency Virus With Atrial Fibrillation: A Review of Its Implications for Clinical Practice.

In the last few decades, types of diseases affecting people living with human immunodeficiency virus (PLHIV) have shifted as the population ages, with cardiovascular disease becoming a leading cause of death in this population. Atrial fibrillation (AF) is an increasingly common arrhythmia both in the general population and in PLHIV, with an estimated prevalence of 2% to 3% among PLHIV. Prevention of stroke and systemic thromboembolism (SSE) with antithrombotic therapy is a cornerstone of AF treatment and substantially decreases AF-related morbidity and mortality. Although updated guidelines extensively discuss this issue, they do not address the peculiarities of PLHIV. The role of human immunodeficiency virus (HIV) infection as an independent factor for SSE in individuals with AF and whether the presence of HIV should alter the threshold for SSE thromboprophylaxis are unknown. Nevertheless, a growing body of evidence describes the increasing burden of comorbidities such as hypertension and stroke in PLHIV, which predispose them to AF and SSE. In the absence of HIV-specific AF guidelines, PLHIV with AF should be comprehensively assessed for their risk of SSE and bleeding using commonly available scores despite them having been primarily validated in the non-HIV population. Both vitamin K antagonists and direct oral anticoagulants can be used in PLHIV. Addressing HIV-related comorbidities and potential drug-drug interactions with antiretrovirals is crucial to prevent SSE and reduce adverse reactions of oral anticoagulants. This review summarizes the current guidelines for SSE prevention in patients with AF and describes key considerations for their implementation among PLHIV receiving antiretroviral therapy.

Au cours des dernières décennies, les types de maladies qui touchent les personnes vivant avec le virus de l'immunodéficience humaine (PVVIH) ont évolué à mesure que la population vieillit. Les maladies cardiovasculaires deviennent ainsi les principales causes de décès dans cette population. La fibrillation auriculaire (FA) est une arythmie de plus en plus fréquente dans la population générale et chez les PVVIH. On estime que sa prévalence est de 2 % à 3 % chez les PVVIH. La prévention de l'accident vasculaire cérébral (AVC) et de la thrombo-embolie systémique (TES) par un traitement antithrombotique constitue la pierre angulaire du traitement de la FA et diminue considérablement la morbidité et la mortalité liées à la FA. Bien que les lignes directrices actualisées traitent en profondeur de cette question, elles ne portent pas sur les particularités des PVVIH. On ignore si l'infection par le virus de l'immunodéficience humaine (VIH) est un facteur indépendant de la TES chez les individus atteints de FA et si la présence du VIH devrait contribuer à modifier le seuil de thromboprophylaxie de la TES. Néanmoins, de plus en plus de données probantes décrivent le fardeau accru des comorbidités comme l'hypertension et l'AVC chez les PVVIH, qui les prédisposent à la FA et à la TES. En l'absence de lignes directrices en matière de FA lors de VIH, on devrait réaliser une évaluation exhaustive chez les PVVIH atteints de FA à l'aide des scores couramment disponibles même s'ils n'avaient pas d'abord été validés auprès de la population non atteinte du VIH. Les antagonistes de la vitamine K et les anticoagulants oraux directs peuvent être utilisés chez les PVVIH. Il est primordial de se pencher sur les comorbidités liées au VIH et sur les interactions médicamenteuses potentielles avec les antirétroviraux pour prévenir la TES et réduire les effets indésirables des anticoagulants oraux. La présente revue résume les lignes directrices actuelles en matière de prévention de la TES chez les patients atteints de FA et décrit les principales considérations quant à leur mise en œuvre auprès des PVVIH qui reçoivent un traitement antirétroviral.