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Little is known about how the co-occurrence of psychosocial factors affect sub-populations of people living with HIV (PLWH). We used cross-sectional data from 999 PLWH, aged ≥19, accessing antiretroviral therapy (ART) in British Columbia, Canada (2007-2010) to examine associations between psychosocial factors and ART-related outcomes separately for trans/cis inclusive women; heterosexual men; and gay, bisexual, and other men who have sex with men (gbMSM). Multivariable logistic regression examined associations between psychosocial factors (0-3): any violence in the past 6 months, depressive symptoms in the past week, and current street drug use (heroin, crack, meth or speedball) with sub-optimal adherence (outcome 1: average annual ART adherence95% from interview until end of follow-up, death, or December 31st, 2018) and ever viral rebound (outcome 2) adjusting for potential confounders. Of 999 PLWH (264 women, 382 heterosexual men, and 353 gbMSM), women and heterosexual men had significantly higher median counts than gbMSM. Overall, higher counts were associated with sub-optimal adherence (adjusted odds ratio [aOR] = 1.26/1-unit increase, 95%CI = 1.07-1.49). All effect estimates were of a greater magnitude among gbMSM, but not significant for women or heterosexual men, highlighting the need for population (e.g., gender and sexual orientation)-centered care and research.

We aimed to characterize mortality among people with HIV (PWH) and psychotic disorders (PWH/psychosis+) vs. PWH alone (PWH/psychosis-).A population-based analysis of mortality in PWH (age ≥19) in British Columbia (BC) from April 1996 to March 2017 was conducted using data from the Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV/AIDS) study. Deaths were identified from the Vital Statistics Data (classified as HIV vs. non-HIV causes). Mortality trends across all fiscal years were examined. Cox models assessed the hazard of psychotic disorders on mortality; possible differences between schizophrenia and nonschizophrenia types of psychotic disorders were also evaluated.Among 13 410 PWH included in the analysis, 1572 (11.7%) met the case definition for at least one psychotic disorder. Over the study period, 3274 deaths (PWH/psychosis-: n = 2785, PWH/psychosis+: n = 489) occurred. A decline over time in all-cause mortality and HIV-related mortality was observed in both PWH/psychosis+ and PWH/psychosis- ( P value0.0001). A decline in non-HIV mortality was observed among PWH/psychosis- ( P value = 0.003), but not PWH/psychosis+ ( P value = 0.3). Nonschizophrenia psychotic disorders were associated with increased risk of mortality; adjusted hazard ratios with (95% confidence intervals): all-cause 1.75 (1.46-2.09), HIV-related 2.08 (1.60-2.69), non-HIV-related 1.45 (1.11-1.90). Similar associations between schizophrenia and mortality were not observed.People with co-occurring HIV and nonschizophrenia psychotic disorders experienced a significantly higher risk of mortality vs. PWH without any psychotic disorder. Implementing care according to syndemic models considering interactions between HIV and particularly episodic psychotic disorders could help manage mortality risk more effectively among PWH/psychosis+.

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.

In 2016, the British Columbia HIV/AIDS Drug Treatment Program modified its prescriber alert system for antiretroviral therapy (ART) interruptions to include referrals to regional public health nursing teams for direct outreach support for those who remain off treatment for 4 months or longer. We evaluated clinically relevant outcomes of this Re-Engagement and Engagement in Treatment for Antiretroviral Interrupted and Naïve populations (RETAIN) initiative, in comparison to previous time-periods.We analyzed ART interruptions triggering alerts in pre-RETAIN (July 2013-April 2016) and post-RETAIN periods (May 2016-October 2017) with follow-up continuing until October 2018. We compared the proportions of those who restarted ART and achieved viral suppression in pre-RETAIN and post-RETAIN periods and the time to ART restart using generalized estimating equations. Cox proportional hazards modelling was used to examine associations with time-to-ART-restart.A total of 1805 individuals experienced ART interruptions triggering 3219 alerts; 2050 in pre-RETAIN and 1169 in post-RETAIN periods. Participants were predominantly men (74%) and had a median duration of ART of 5 years. Among persons who remained interrupted4 months after an ART interruption alert was sent, the median time from interruption to ART re-initiation declined from 8.7 months to 7.4 months (P0.001) from pre-to post-RETAIN periods. Interruptions in the post-RETAIN era were associated with an increased hazard of restarting ART (adjusted hazard ratio 1.51; 95% CI: 1.34 to 1.69).Public health referrals shortened the length of ART interruptions after alerts sent to prescribers had not resulted in re-engagement. Similar programs should be considered in other jurisdictions.

Background: Advances in treatment have turned HIV from a terminal illness to a more manageable condition. Over the past 20 years, there have been considerable changes to HIV treatment guidelines, including changes in preferred antiretrovirals and timing of initiation of combination antiretroviral therapy (cART). Objective: To examine real-world trends in cART utilization, viral control, and immune reconstitution among people living with HIV in Canada. Methods: Data were obtained from the Canadian Observational Cohort (CANOC). CANOC participants were eligible if they were antiretroviral therapy–naive at entry and initiated 3 or more antiretrovirals on or after January 1, 2000; if they were at least 18 years of age at treatment initiation; if they were residing in Canada; and if they had at least 1 viral load determination and CD4 count within 1 year of CANOC entry. Baseline and annual mean CD4 counts were categorized as less than 200, 200–350, 351–500, and more than 500 cells/mm3. Annual mean viral loads were reported as suppressed (

Background Routine HIV drug resistance genotyping identified an integrase sequence harbouring T97A, E138K, G140S and Q148H, with high predicted resistance to all integrase strand transfer inhibitors (INSTIs). Objectives To assess the impact of these substitutions alone and together on phenotypic INSTI susceptibility. Methods We constructed recombinant NL4.3 viruses harbouring all mutation combinations in the autologous integrase sequence. Viruses were grown in GFP-reporter CD4+ T-cells in the presence of 0.01–1000 nM raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir. Infection was measured by imaging cytometry. Results Q148H-containing viruses lacking G140S failed to propagate or mutated in vitro, consistent with fitness costs. Statistically significant reductions in INSTI susceptibility were observed for several mutation combinations, as follows. T97A or G140S alone conferred 3.6- to 5.6-fold decreased susceptibility to raltegravir and elvitegravir. Two-mutation combinations conferred low-to-moderate resistance to raltegravir and elvitegravir only, except G140S/Q148H which eliminated raltegravir and elvitegravir activity and conferred 24.6-, 7.9-, and 107.5-fold reduced susceptibility to dolutegravir, bictegravir and cabotegravir. Addition of E138K to G140S/Q148H conferred 35.5, 11.6 and 208-fold reduced susceptibility to dolutegravir, bictegravir, and cabotegravir, while addition of T97A to G140S/Q148H conferred 318, 121 and >1000-fold reduced susceptibility to these drugs. T97A/E138K/G140S/Q148H in the autologous backbone conferred >300-fold reduced susceptibility to all INSTIs. Notably, bictegravir EC50 was significantly lower when T97A/E138K/G140S/Q148H was introduced into NL4.3, suggesting that other mutations in the autologous sequence enhanced resistance. Conclusions High-level dolutegravir, bictegravir and cabotegravir resistance requires multiple integrase substitutions including compensatory mutations. T97A and E138K further enhance the resistance conferred by G140S/Q148H, yielding >300-fold decreased susceptibility to all INSTIs when all four mutations are present.

Background and objectives Public health officials faced with a large number of transmission clusters require a rapid, scalable and unbiased way to prioritize distribution of limited resources to maximize benefits. We hypothesize that transmission cluster prioritization based on phylogenetically derived lineage-level diversification rates will perform as well as or better than commonly used growth-based prioritization measures, without need for historical data or subjective interpretation. Methodology 9822 HIV pol sequences collected during routine drug resistance genotyping were used alongside simulated sequence data to infer sets of phylogenetic transmission clusters via patristic distance threshold. Prioritized clusters inferred from empirical data were compared to those prioritized by the current public health protocols. Prioritization of simulated clusters was evaluated based on correlation of a given prioritization measure with future cluster growth, as well as the number of direct downstream transmissions from cluster members. Results Empirical data suggest diversification rate-based measures perform comparably to growth-based measures in recreating public heath prioritization choices. However, unbiased simulated data reveals phylogenetic diversification rate-based measures perform better in predicting future cluster growth relative to growth-based measures, particularly long-term growth. Diversification rate-based measures also display advantages over growth-based measures in highlighting groups with greater future transmission events compared to random groups of the same size. Furthermore, diversification rate measures were notably more robust to effects of decreased sampling proportion. Conclusions and implications Our findings indicate diversification rate-based measures frequently outperform growth-based measures in predicting future cluster growth and offer several additional advantages beneficial to optimizing the public health prioritization process.

BackgroundLonger-term immune response data after 3 doses of coronavirus disease 2019 (COVID-19) mRNA vaccine remain limited, particularly among older adults and after Omicron breakthrough infection.MethodsWe quantified wild-type- and Omicron-specific serum immunoglobulin (Ig)G levels, angiotensin-converting enzyme 2 displacement activities, and live virus neutralization up to 6 months after third dose in 116 adults aged 24–98 years who remained COVID-19 naive or experienced their first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during this time.ResultsAmong the 78 participants who remained COVID-19 naive throughout follow up, wild-type- and Omicron-BA.1-specific IgG concentrations were comparable between younger and older adults, although BA.1-specific responses were consistently significantly lower than wild-type-specific responses in both groups. Wild-type- and BA.1-specific IgG concentrations declined at similar rates in COVID-19-naive younger and older adults, with median half-lives ranging from 69 to 78 days. Antiviral antibody functions declined substantially over time in COVID-19-naive individuals, particularly in older adults: by 6 months, BA.1-specific neutralization was undetectable in 96% of older adults, versus 56% of younger adults. Severe acute respiratory syndrome coronavirus 2 infection, experienced by 38 participants, boosted IgG levels and neutralization above those induced by vaccination alone. Nevertheless, BA.1-specific neutralization remained significantly lower than wild-type, with BA.5-specific neutralization lower still. Higher Omicron BA.1-specific neutralization 1 month after third dose was an independent correlate of lower SARS-CoV-2 infection risk.ConclusionsResults underscore the immune benefits of the third COVID-19 mRNA vaccine dose in adults of all ages and identify vaccine-induced Omicron-specific neutralization as a correlate of protective immunity. Systemic antibody responses and functions however, particularly Omicron-specific neutralization, decline rapidly in COVID-19-naive individuals, particularly in older adults, supporting the need for additional booster doses.

HIV treatment interruptions are a

Background and objectives Although HIV sequence clustering is routinely used to identify subpopulations experiencing elevated transmission, it over-simplifies transmission dynamics and is sensitive to methodology. Complementarily, viral diversification rates can be used to approximate historical transmission rates. Here, we investigated the concordance and sensitivity of HIV transmission risk factors identified by phylogenetic clustering, viral diversification rate, changes in viral diversification rate and a combined approach. Methodology Viral sequences from 9848 people living with HIV in British Columbia, Canada, sampled between 1996 and February 2019, were used to infer phylogenetic trees, from which clusters were identified and viral diversification rates of each tip were calculated. Factors associated with heightened transmission risk were compared across models of cluster membership, viral diversification rate, changes in diversification rate, and viral diversification rate among clusters. Results Viruses within larger clusters had higher diversification rates and lower changes in diversification rate than those within smaller clusters; however, rates within individual clusters, independent of size, varied widely. Risk factors for both cluster membership and elevated viral diversification rate included being male, young, a resident of health authority E, previous injection drug use, previous hepatitis C virus infection or a high recent viral load. In a sensitivity analysis, models based on cluster membership had wider confidence intervals and lower concordance of significant effects than viral diversification rate for lower sampling rates. Conclusions and implications Viral diversification rate complements phylogenetic clustering, offering a means of evaluating transmission dynamics to guide provision of treatment and prevention services. Lay Summary Understanding HIV transmission dynamics within clusters can help prioritize public health resource allocation. We compared socio-demographic and clinical risk factors associated with phylogenetic cluster membership and viral diversification rate, a historical branching rate, in order to assess their relative concordance and sampling sensitivity.

Background: Risk compensation in an HIV Treatment as Prevention (TasP) environment may increase high-risk sexual and substance use behaviors among people living with HIV. Objective: To examine recent crystal methamphetamine (CM) use/initiation in a longitudinal cohort of gay, bisexual, and other men who have sex with men (GBMSM) living with HIV in Metro Vancouver, Canada. Methods: Eligible participants were GBMSM aged >15years who reported sex with another man in the past six months. Participants were recruited using respondent-driven sampling and self-completed a computer questionnaire every six months. We used multi-level generalized mixed-effect models to evaluate trends in recent CM use (past six months), multivariable logistic regression to identify covariates of recent CM use, and multivariable survival analysis to identify predictors of CM initiation. Results: Of 207 GBMSM living with HIV at enrollment, 44.3% reported recent CM use; there was a statistically non-significant decrease over the study period (41% in first period to 25% in final period, p=0.087). HIV treatment optimism was not associated with CM use/initiation. CM use was positively associated with depressive symptomology, sexual escape motivation, transactional sex, number of anal sex partners, condomless anal sex with seroconcordant partners, STIs, and other substance use. Recent CM use was negatively associated with viral load sorting. CM initiation was predicted by escape motivation, transactional sex, and group sex participation. Conclusion: Results suggest that CM use among GBMSM living with HIV is prevalent and increased CM use/initiation is not a consequence of TasP public policy.

Abacavir hypersensitivity syndrome (ABC HSS) is strongly associated with carriage of human leukocyte antigen (HLA)-B*57:01, which has a 100% negative predictive value for the development of ABC HSS. However, 45% of individuals who carry HLA-B*57:01 can tolerate ABC. We investigated immune and non-immune related genes in ABC HSS (n = 95) and ABC tolerant (n = 43) HLA-B*57:01 + patients to determine other factors required for the development of ABC HSS. Assignment of phenotype showed that ABC HSS subjects were significantly less likely than tolerants to carry only ERAP1 hypoactive trimming allotypes (p = 0.02). An altered self-peptide repertoire model by which abacavir activates T cells is in keeping with observation that endoplasmic reticulum aminopeptidase 1 (ERAP1) allotypes that favour efficient peptide trimming are more common in ABC HSS patients compared to patients who tolerate ABC. Independently, non-specific immune activation via soluble cluster of differentiation antigen 14 (sCD14) may also influence susceptibility to ABC HSS.

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.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/mmThis 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.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.

ObjectivesNon-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 settingA population-based cohort study in British Columbia, Canada.MethodsEligible 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 measuresA 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.ResultsAmong 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).ConclusionsOur 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.

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/mm3. Nadir CD4+ T-cell counts ranged as low as 3. After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was significantly associated with 0.2 log10 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.

BackgroundmRNA vaccines reduce COVID-19 incidence and severity, but the durability of vaccine-induced immune responses, particularly among the elderly, remains incompletely characterized.MethodsAnti-spike RBD antibody titers, ACE2 competition and virus neutralizing activities were longitudinally assessed in 151 healthcare workers and older adults (overall aged 24-98 years) up to three months after vaccination.ResultsOlder adults exhibited lower antibody responses after one and two vaccine doses for all measures. In multivariable analyses correcting for sociodemographic, chronic health and vaccine-related variables, age remained independently associated with all response outcomes. The number of chronic health conditions was additionally associated with lower binding antibody responses after two doses, and male sex with lower ACE2 competition activity after one dose. Responses waned universally at three months after the second dose, but binding antibodies, ACE2 competition and neutralizing activities remained significantly lower with age. Older adults also displayed reduced ability to block ACE2 binding by the Delta variant.ConclusionsThe humoral immune response to COVID-19 mRNA vaccines is significantly weaker with age, and universally wanes over time. This will likely reduce antibody-mediated protection against SARS-CoV-2 and the Delta variant as the pandemic progresses. Older adults may benefit from additional immunizations as a priority.

Background The magnitude and durability of immune responses to coronavirus disease 2019 (COVID-19) mRNA vaccines remain incompletely characterized in the elderly. Methods Anti-spike receptor-binding domain (RBD) antibodies, angiotensin-converting enzyme 2 (ACE2) competition, and virus neutralizing activities were assessed in plasma from 151 health care workers and older adults (range, 24–98 years of age) 1 month following the first vaccine dose, and 1 and 3 months following the second dose. Results Older adults exhibited significantly weaker responses than younger health care workers for all humoral measures evaluated and at all time points tested, except for ACE2 competition activity after 1 vaccine dose. Moreover, older age remained independently associated with weaker responses even after correction for sociodemographic factors, chronic health condition burden, and vaccine-related variables. By 3 months after the second dose, all humoral responses had declined significantly in all participants, and remained significantly lower among older adults, who also displayed reduced binding antibodies and ACE2 competition activity towards the Delta variant. Conclusions Humoral responses to COVID-19 mRNA vaccines are significantly weaker in older adults, and antibody-mediated activities in plasma decline universally over time. Older adults may thus remain at elevated risk of infection despite vaccination.

Sharing used syringes is an important route of HIV transmission, however, factors shaping used syringe-lending among antiretroviral therapy (ART)-naïve HIV-positive people who inject drugs (PWID) are not well-characterized. Multivariable logistic regression analyses using generalized estimating equations (GEE) were employed to investigate correlates of used syringe lending among ART-naïve PWID. Data was drawn from ACCESS, a prospective community-recruited cohort of HIV-positive illicit drug users in Vancouver, Canada, from 1996 to 2015. The analysis included 482 ART-naïve PWID, of which 116 (24.1%) reported ≥ 1 periods of used syringe lending. In longitudinal analyses, incarceration (Adjusted Odds Ratio [AOR] = 2.18, 95% Confidence Interval [CI] 1.48–3.20), daily cocaine injection (AOR= 1.97, 95% CI 1.33–2.90), and sex work (AOR = 1.61, 95% CI 1.02–2.55) during the 180-day observation period were positively associated with used syringe lending, while having a high school diploma (AOR = 0.63, 95% CI 0.43–0.93) and holding formal employment (AOR = 0.20, 95% CI 0.05–0.82) were negatively associated. We found a high prevalence of used syringe lending among ART-naïve HIV-positive PWID, particularly among those recently incarcerated, involved in sex work or who injected cocaine frequently. Conversely, markers of higher socio-economic status were negatively associated with used syringe lending. These findings highlight the critical need for policies and interventions to decrease socio-economic marginalization and criminalization among PWID living with HIV alongside the scale up of access to harm reduction services.

Background: Identifying populations at high risk of HIV transmission is critical for prioritizing treatment and prevention resources and achieving the UNAIDS 90-90-90 Targets. Methods: HIV transmission rates can be estimated from phylogenetic trees as viral lineage-level diversification rates. To identify HIV-1 transmission foci in British Columbia, Canada, we inferred diversification rates from phylogenetic trees of 36 271 HIV-1 sequences from 9630 anonymized individuals. Diversification rates were combined with sociodemographic and clinical data, then aggregated by patients’ area of residence to predict the distribution of new HIV cases between 2008 and 2018. The predictive power of the model was compared with a phylogenetically uninformed model. Findings: Aggregated diversification rate measures were predictive of new HIV cases in the subsequent year after adjusting for prevalent and incident cases in the previous year. For every one-unit increase in the mean of the top five diversification rates, the number of new HIV cases increased by on average 1·38-fold (95% CI, 1·28–1·49). In a blind prediction of 2018 cases, diversification rate improved the model's specificity by 12%, accuracy by 9%, top 20 agreement by 100%, and correlation of predicted and observed values by 162% relative to a model that incorporated epidemiological data alone. Interpretation: By predicting the distribution of future HIV cases, a combined phylogenetic and epidemiological approach identifies hotspots where public health resources are needed most. Funding: Canadian Institutes of Health Research, University of British Columbia, Public Health Agency of Canada, Genome Canada, Genome BC, Michael Smith Foundation for Health Research, and BC Centre for Excellence in HIV/AIDS. Keywords: HIV, Phylogenetics, Epidemiology, Transmission, Predictive model

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. Résumé: 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.

Objective: To characterize the incidence of select chronic comorbidities in the era of modern (pre-integrase-inhibitor) highly active antiretroviral therapy (HAART) in British Columbia, Canada.Meth...

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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.17269/s41997-019-00253-w) contains supplementary material, which is available to authorized users.

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. Keywords: HIV, Integrase inhibitors, Virologic suppression, Transmission risk, Mathematical modeling, gbMSM

Schizophrenia is a severe mental illness with important implications for morbidity and mortality. This population-based cohort study examined the impact of schizophrenia diagnoses on all-cause mortality among a sample of people living with HIV (PLHIV) and a 10% random sample of individuals living without HIV (HIV-) in British Columbia (BC), through a data linkage between the BC Centre for Excellence in HIV/AIDS and Population Data BC's data holdings. Schizophrenia diagnoses were identified via International Classification of Diseases version 9 and version 10 codes. Age- and sex-adjusted all-cause mortality rates from January 1st, 1998 to December 31st, 2012 were calculated. Multivariable logistic models assessed (1) HIV status and mortality among individuals diagnosed with schizophrenia, (2) schizophrenia diagnosis and mortality among PLHIV, and (3) correlates of mortality among PLHIV concurrently diagnosed with schizophrenia (HIV+/SZO+). From 1998 to 2012, 6.3% of those with HIV had a schizophrenia diagnosis, compared to 1.1% of those without HIV. While significant declines in mortality rates were observed throughout the study period, mortality rates were highest among HIV+/SZO+. After adjustment for substance use disorder and age at baseline, HIV+/SZO+ had a 2.64 times greater odds of mortality (95% confidence interval [CI] = 2.14–3.25) compared to HIV-/SZO+. For PLHIV, a schizophrenia diagnosis was not associated with mortality after controlling for potential confounders (adjusted odds ratio [aOR] = 0.90, 95%CI = 0.74–1.09). Among HIV+/SZO+, age, history of injection drug use, ever having an AIDS-defining illness, and never being on anti-psychotic medication or accessing psychiatric services were associated with mortality. Efforts should be made to identify and link to care individuals disproportionately affected by schizophrenia and excess mortality, including those living with HIV.

Borne out of a necessity for fiscal sustainability, simulation modeling is playing an increasingly prominent role in setting priorities for combination implementation strategies for HIV treatment and prevention globally. The design of a model and the data inputted into it are central factors in ensuring credible inferences. We executed a narrative review of a set of dynamic HIV transmission models to comprehensively synthesize and compare the structural design and the quality of evidence used to support each model. We included nineteen models representing both generalized and concentrated epidemics, classified as compartmental, agent-based, individual-based microsimulation or hybrid in our review. We focused on four structural components (population construction; model entry, exit and HIV care engagement; HIV disease progression; and the force of HIV infection), and two analytical components (model calibration/validation; and health economic evaluation, including uncertainty analysis). While the models we reviewed focused on a variety of individual interventions and their combinations, their structural designs were relatively homogenous across three of the four focal components, with key structural elements influenced by model type and epidemiological context. In contrast, model entry, exit and HIV care engagement tended to differ most across models, with some health system interactions –particularly HIV testing– not modeled explicitly in many contexts. The quality of data used in the models, and the transparency with which the data was presented differed substantially across model components. Representative and high-quality data on health service delivery was most commonly not accessed or unavailable. The structure of an HIV model should ideally fit its epidemiological context and be able to capture all efficacious treatment and prevention services relevant to a robust combination implementation strategy. Developing standardized guidelines on evidence syntheses for health economic evaluation would improve transparency and help prioritize data collection to reduce decision uncertainty.

Longer survival has increased the likelihood of antiretroviral-treated people living with HIV (PLWH) developing age-associated comorbidities. We compared the burden of multimorbidity and all-cause mortality across HIV status in British Columbia (BC), and assessed the longitudinal effect of multimorbidity on all-cause mortality among PLWH.Antiretroviral-treated PLWH aged ≥19 years and 1:4 age-sex-matched HIV-negative individuals from a population-based cohort were followed for ≥1 year during 2001-2012. Diagnoses of seven age-associated comorbidities were identified from provincial administrative databases and grouped into 0, 1, 2, and ≥3 comorbidities. Multimorbidity prevalence and age-standardized mortality rates (ASMRs) in both populations were stratified by BC's health regions. Marginal structural models were used to estimate the effect of multimorbidity on mortality among PLWH, adjusted for time-varying confounders affected by prior multimorbidity.Among 8031 PLWH and 32,124 HIV-negative individuals, 25% versus 11% developed multimorbidity, and 23.53 deaths/1000 person-years (95% confidence interval [95% CI]: 22.02-25.13) versus 3.04 (2.81-3.29) were observed, respectively. PLWH in Northern region had the highest ASMR, but those in South Vancouver Island experienced the greatest difference in mortality compared with HIV-negative individuals. Among PLWH, compared with those with zero comorbidities, adjusted hazard ratios for those with 1, 2, and ≥3 comorbidities were 3.36 (95% CI: 2.86-3.95), 6.92 (5.75-8.33), and 12.87 (10.45-15.85), respectively.PLWH across BC's health regions experience excess multimorbidity and associated mortality. We highlight health disparities which are key when planning the distribution of healthcare resources across BC, and provide evidence for improved HIV care models integrating prevention and management of chronic diseases.RéSUMé: OBJECTIF: Les nouvelles thérapeutiques antirétrovirales (ARV) ont permis une plus longue espérance de vie aux personnes porteuses du VIH. Cependant, le vieillissement augmente la probabilité de développer des comorbidités au sein même de la population des personnes vivant avec le VIH (PVVIH) qui suivent des traitements ARV. On a comparé le fardeau de la multimorbidité et mortalité, toutes causes confondues, lié au statut VIH à travers la Colombie-Britannique. On a aussi évalué l’effet longitudinal de la multimorbidité sur la mortalité, toutes causes confondues, parmi les PVVIH. MéTHODES: L’étude comprit des PVVIH suivant un traitement ARV âgés de ≥19 ans et un groupe témoin séronégatif (4 témoins par PVVIH) comparable en termes d’âge et de sexe, tous provenant d’une cohorte de surveillance continue d’au moins 1 an sur une période allant de 2001 à 2012. Des diagnostics de sept comorbidités liées à l’âge ont été identifiés à partir des bases de données administratives provinciales et regroupés en 0, 1, 2 et ≥3 comorbidités. La prévalence de la multimorbidité et les taux de mortalité normalisés selon l’âge (TMNA) dans les deux populations ont été stratifiés selon les régions sociosanitaires de la Colombie-Britannique. Des modèles structurels marginaux ont été utilisés pour estimer l’effet de la multimorbidité sur la mortalité chez les PVVIH, ajustant pour les facteurs de confusion variables affectés par une multimorbidité antérieure. RéSULTATS: Parmi 8 031 PVVIH et 32 124 personnes séronégatives pour le VIH, 25 % contre 11 % ont développé une multimorbidité et 23,53 décès pour 1 000 personnes-années (intervalle de confiance à 95 % [IC à 95 %]: 22,02–25,13) contre 3,04 (2,81–3,29) ont été observés, respectivement. Les PVVIH de la région septentrionale avaient le TMNA le plus élevé, alors que ceux du sud de l’île de Vancouver ont connu la plus grande différence de mortalité par rapport aux personnes séronégatives. Parmi les PVVIH, les personnes atteintes de 1, 2 et ≥3 comorbidités avaient respectivement 3,36 (IC à 95 %: 2,86–3,95), 6,92 (5,75–8,33) et 12,87 (10,45–15,85) fois plus la probabilité de mourir que les personnes sans comorbidités. CONCLUSION: Les PVVIH des régions sociosanitaires de la Colombie-Britannique connaissent une multimorbidité excessive et la surmortalité s’y associant. Notre étude souligne les disparités-clés en matière de santé qu’il faut prendre en compte lors de la planification de la distribution des ressources de soins de santé à travers la Colombie-Britannique. Elle fournit aussi des preuves pour des modèles de soins du VIH améliorés, y intégrant la prévention et la gestion des maladies chroniques.

Men who have sex with men (MSM) are at risk for sexually-transmitted hepatitis C (HCV). Evidence for HCV infection in the context of pre-exposure prophylaxis (PrEP) use in North America is limited. We sought to characterize baseline HCV prevalence and incidence in MSM receiving PrEP in British Columbia (BC), Canada.We followed individuals in the BC PrEP program from January 2018 to August 2019. We evaluated baseline prevalence and incident seroconversions (newly positive HCV antibody). A multivariable logistic regression model was performed in MSM for factors associated with HCV prevalence at enrollment, including reported prior sexually transmitted infection (STI), HIV Incidence Risk Index for MSM score, PrEP use because of a partner living with HIV, and location of residence.The median age of the cohort was 33 years, 98.3% male, with 3058 person years (PY) of follow-up. Baseline HCV prevalence was 0.82% (31/3907 MSM enrollees) and HCV incidence (n = 3) was 0.15 per 100 PY (95% confidence interval [CI] 0.03-0.45). In multivariable analysis, initiating PrEP because of a partner living with HIV (adjusted odds ratio [aOR] 5.02; 95% CI 1.87-13.47) and prior STI (aOR 2.34; 95% CI 1.04-5.24) were associated with positive HCV status.Baseline HCV prevalence and incidence was low amongst MSM in a population-based PrEP program in BC, Canada. HCV was associated with bridging from populations living with HIV and evidence of a reported prior STI as a PrEP indicator condition amongst MSM. PrEP initiation may be an opportunity for linkage to HCV screening and treatment.

Background The updated Veterans Aging Cohort Study (VACS) Index 2.0 combines general and human immunodeficiency virus (HIV)–specific biomarkers to generate a continuous score that accurately discriminates risk of mortality in diverse cohorts of persons with HIV (PWH), but a score alone is difficult to interpret. Using data from the North American AIDS Cohort Collaboration (NA-ACCORD), we translate VACS Index 2.0 scores into validated probability estimates of mortality. Methods Because complete mortality ascertainment is essential for accurate calibration, we restricted analyses to cohorts with mortality from the National Death Index or equivalent sources. VACS Index 2.0 components were ascertained from October 1999 to April 2018. Mortality was observed up to March 2019. Calibration curves compared predicted (estimated by fitting a gamma model to the score) to observed mortality overall and within subgroups: cohort (VACS/NA-ACCORD subset), sex, age 500 copies/mL, CD4 count Results Among 37230 PWH in VACS and 8061 PWH in the NA-ACCORD subset, median age was 53 and 44 years; 3% and 19% were women; and 48% and 39% were black. Discrimination in NA-ACCORD (C-statistic = 0.842 [95% confidence interval {CI}, .830–.854]) was better than in VACS (C-statistic = 0.813 [95% CI, .809–.817]). Predicted and observed mortality largely overlapped in VACS and the NA-ACCORD subset, overall and within subgroups. Conclusions Based on this validation, VACS Index 2.0 can reliably estimate probability of all-cause mortality, at various follow-up times, among PWH in North America.

Quantitative viral load assays have transformed our understanding of – and ability to manage − viral diseases. They hold similar potential to advance COVID-19 control and prevention, but SARS-CoV-2 viral load tests are not yet widely available. SARS-CoV-2 molecular diagnostic tests, which typically employ real-time reverse transcriptase-polymerase chain reaction (RT-PCR), yield semi-quantitative results only. Reverse transcriptase droplet digital PCR (RT-ddPCR), a technology that partitions each reaction into 20,000 nanolitre-sized droplets prior to amplification, offers an attractive platform for SARS-CoV-2 RNA quantification. We evaluated eight primer/probe sets originally developed for real-time RT-PCR-based SARS-CoV-2 diagnostic tests for use in RT-ddPCR, and identified three (Charité-Berlin E-Sarbeco and Pasteur Institute IP2 and IP4) as the most efficient, precise and sensitive for RT-ddPCR-based SARS-CoV-2 RNA quantification. Analytical efficiency of the E-Sarbeco primer/probe set, for example, was ~83%, while assay precision, as measured by the coefficient of variation, was ~2% at 1000 input copies/reaction. Lower limits of quantification and detection for this primer/probe set were 18.6 and 4.4 input SARS-CoV-2 RNA copies/reaction, respectively. SARS-CoV-2 RNA viral loads in a convenience panel of 48 COVID-19-positive diagnostic specimens spanned a 6.2log10 range, confirming substantial viral load variation in vivo. We further calibrated RT-ddPCR-derived SARS-CoV-2 E gene copy numbers against cycle threshold (Ct) values from a commercial real-time RT-PCR diagnostic platform. The resulting log-linear relationship can be used to mathematically derive SARS-CoV-2 RNA copy numbers from Ct values, allowing the wealth of available diagnostic test data to be harnessed to address foundational questions in SARS-CoV-2 biology.