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Phylogenetics has been advanced as a structural framework to infer evolving trends in the regional spread of HIV-1 and guide public health interventions. In Quebec, molecular network analyses tracked HIV transmission dynamics from 2002-2020 using MEGA10-Neighbour-joining, HIV-TRACE, and MicrobeTrace methodologies. Phylogenetics revealed three patterns of viral spread among Men having Sex with Men (MSM, n = 5024) and heterosexuals (HET, n = 1345) harbouring subtype B epidemics as well as B and non-B subtype epidemics (n = 1848) introduced through migration. Notably, half of new subtype B infections amongst MSM and HET segregating as solitary transmissions or small cluster networks (2-5 members) declined by 70% from 2006-2020, concomitant to advances in treatment-as-prevention. Nonetheless, subtype B epidemic control amongst MSM was thwarted by the ongoing genesis and expansion of super-spreader large cluster variants leading to micro-epidemics, averaging 49 members/cluster at the end of 2020. The growth of large clusters was related to forward transmission cascades of untreated early-stage infections, younger at-risk populations, more transmissible/replicative-competent strains, and changing demographics. Subtype B and non-B subtype infections introduced through recent migration now surpass the domestic epidemic amongst MSM. Phylodynamics can assist in predicting and responding to active, recurrent, and newly emergent large cluster networks, as well as the cryptic spread of HIV introduced through migration.

: Introduction: HIV pre‐exposure prophylaxis (PrEP) has been recommended and partly subsidized in Québec, Canada, since 2013. We evaluated the population‐level impact of PrEP on HIV transmission among men who have sex with men (MSM) in Montréal, Québec's largest city, over 2013–2021. Methods: We used an agent‐based mathematical model of sexual HIV transmission to estimate the fraction of HIV acquisitions averted by PrEP compared to a counterfactual scenario without PrEP. The model was calibrated to local MSM survey, surveillance, and cohort data and accounted for COVID‐19 pandemic impacts on sexual activity, HIV prevention, and care. PrEP was modelled from 2013 onwards, assuming 86% individual‐level effectiveness. The PrEP eligibility criteria were: any anal sex unprotected by condoms (past 6 months) and either multiple partnerships (past 6 months) or multiple uses of post‐exposure prophylaxis (lifetime). To assess potential optimization strategies, we modelled hypothetical scenarios prioritizing PrEP to MSM with high sexual activity (≥11 anal sex partners annually) or aged ⩽45 years, increasing coverage to levels achieved in Vancouver, Canada (where PrEP is free‐of‐charge), and improving retention. Results: Over 2013–2021, the estimated annual HIV incidence decreased from 0.4 (90% credible interval [CrI]: 0.3–0.6) to 0.2 (90% CrI: 0.1–0.2) per 100 person‐years. PrEP coverage among HIV‐negative MSM remained low until 2015 ( Conclusions: PrEP reduced population‐level HIV transmission among Montréal MSM. However, our study suggests missed prevention opportunities and adds support for public policies that reduce PrEP barriers, financial or otherwise, to MSM at risk of HIV acquisition., INTRODUCTION After over 20 years under study [1–3] and 10 years of availability [4], oral pre‐exposure prophylaxis (PrEP) has proven highly efficacious for preventing HIV acquisition across transmission routes. Rigorous [...]

Background: HIV drug resistance (HIV-DR) may jeopardize the benefit of antiretroviral therapy (ART) in treatment and prevention. This study utilized viral phylogenetics to resolve the influence of transmission networks on sustaining the spread of HIV-DR in Quebec spanning 2002 to 2022. Methods: Time trends in acquired (ADR) and transmitted drug resistance (TDR) were delineated in treatment-experienced (n = 3500) and ART-naïve persons (n = 6011) with subtype B infections. Similarly, non-B-subtype HIV-DR networks were assessed pre- (n = 1577) and post-ART experience (n = 488). Risks of acquisition of resistance-associated mutations (RAMs) were related to clustering using 1, 2–5, vs. 6+ members per cluster as categorical variables. Results: Despite steady declines in treatment failure and ADR since 2007, rates of TDR among newly infected, ART-naive persons remained at 14% spanning the 2007–2011, 2012–2016, and 2017–2022 periods. Notably, half of new infections among men having sex with men and heterosexual groups were linked in large, clustered networks having a median of 35 (14–73 IQR) and 16 (9–26 IQR) members per cluster, respectively. Cluster membership and size were implicated in forward transmission of non-nucleoside reverse transcriptase inhibitor NNRTI RAMs (9%) and thymidine analogue mutations (TAMs) (5%). In contrast, transmission of M184V, K65R, and integrase inhibitors (1–2%) remained rare. Levels of TDR reflected viral replicative fitness. The median baseline viremia in ART-naïve groups having no RAMs, NNRTI RAMs, TAMs, and M184VI were 46.088, 38,447, 20,330, and 6811 copies/mL, respectively (p < 0.0001). Conclusion: Phylogenetics emphasize the need to prioritize ART and pre-exposure prophylaxis strategies to avert the expansion of transmission cascades of HIV-DR. [ABSTRACT FROM AUTHOR]

BackgroundThe genomic heterogeneity of HIV-1 impedes the ability of consensus sequences in vaccines to elicit effective antiviral immune responses. AGS-004 amplifies translation-competent RNA molecules encoding for Gag, Rev, Vpr, and Nef from the patient's autologous virus and loads them into dendritic cells.MethodsThis phase IIB, multicenter, 2:1 randomized, double-blind, placebo-controlled study enrolled 54 HIV-1-infected patients on antiretroviral therapy with viral loads (VLs) 450 cells per cubic millimeter, and nadir counts >200 cells per cubic millimeter, to receive intradermal injections of study product into the axillary lymph node region every 4 weeks. At week 16, a 12-week analytical treatment interruption (ATI) was undertaken.ResultsThere was no difference in the end-of-ATI VL (average of values from weeks 11 and 12) between the 2 arms of the study [4.39 (4.17, 4.69) vs. 4.47 (3.76, 4.64) log10 HIV-1 RNA; P = 0.73]. Between arms, no change between pre-antiretroviral therapy VL and the end-of-ATI VL [-0.06 (0.24, -0.32) vs. -0.17 (0.17, -0.32) log10 HIV-1 RNA; P = 0.43] was observed. When interferon-γ, interleukin-2, tumor necrosis factor α, CD107a, and granzyme b expressions were measured by multicolor flow cytometry, a greater percentage of AGS-004 than of placebo recipients had multifunctional cytotoxic T-lymphocyte responses induced in the CD28+/CD45RA-CD8 effector/memory T-cell population to dendritic cells electroporated with autologous antigens. Adverse events consisted of transient, mild (grade 1) local injection site reactions.ConclusionsDespite the induction of HIV-specific effector/memory CD8 T-cell responses, no antiviral effect was seen after the administration of AGS-004 when compared with placebo.

BackgroundThe genomic heterogeneity of HIV-1 impedes the ability of consensus sequences in vaccines to elicit effective antiviral immune responses. AGS-004 amplifies translation-competent RNA molecules encoding for Gag, Rev, Vpr, and Nef from the patient's autologous virus and loads them into dendritic cells.MethodsThis phase IIB, multicenter, 2:1 randomized, double-blind, placebo-controlled study enrolled 54 HIV-1-infected patients on antiretroviral therapy with viral loads (VLs) 450 cells per cubic millimeter, and nadir counts >200 cells per cubic millimeter, to receive intradermal injections of study product into the axillary lymph node region every 4 weeks. At week 16, a 12-week analytical treatment interruption (ATI) was undertaken.ResultsThere was no difference in the end-of-ATI VL (average of values from weeks 11 and 12) between the 2 arms of the study [4.39 (4.17, 4.69) vs. 4.47 (3.76, 4.64) log10 HIV-1 RNA; P = 0.73]. Between arms, no change between pre-antiretroviral therapy VL and the end-of-ATI VL [-0.06 (0.24, -0.32) vs. -0.17 (0.17, -0.32) log10 HIV-1 RNA; P = 0.43] was observed. When interferon-γ, interleukin-2, tumor necrosis factor α, CD107a, and granzyme b expressions were measured by multicolor flow cytometry, a greater percentage of AGS-004 than of placebo recipients had multifunctional cytotoxic T-lymphocyte responses induced in the CD28+/CD45RA-CD8 effector/memory T-cell population to dendritic cells electroporated with autologous antigens. Adverse events consisted of transient, mild (grade 1) local injection site reactions.ConclusionsDespite the induction of HIV-specific effector/memory CD8 T-cell responses, no antiviral effect was seen after the administration of AGS-004 when compared with placebo.

Objectives: Our objective was to report the baseline characteristics of participants in the Canadian HIV and Aging Cohort Study (CHACS) and present amendments to the initial protocol. Methods: CHACS is a multi‐centred prospective cohort study that was initially set from 2011 to 2016 and will now continue recruitment until 2024. Four additional years of follow‐up have been added, and additional outcomes and covariates will be prospectively collected. Frailty will be assessed using a modified version of the Fried's frailty phenotype. The four interrelated aspects of gender—gender roles, gender identity, gender relationships, and institutionalized gender—will be measured using the GENESIS‐PRAXY questionnaire. Diet will be assessed using a validated, web‐based, self‐administered food frequency questionnaire. Results: A total of 1049 participants (77% people living with HIV) were recruited between September 2011 and September 2019. Median age at baseline was 54 years (interquartile range 50–61). Most participants were male (84%) and white (83%). Compared with participants without HIV, those with HIV were more likely to be male; to report lower education levels and incomes; to be more sedentary; to use tobacco, recreational, and prescription drugs; to report a personal history of cardiovascular diseases; and to be frail. Conclusions: The new assessments added to the CHACS protocol will allow for an even more detailed portrait of the pathways leading to accentuated aging for people living with HIV. Participants in the CHACS cohort display important differences in socio‐economic and cardiovascular risk factors according to HIV serostatus. These imbalances must be taken into account for all further inferential analyses. [ABSTRACT FROM AUTHOR]

: Introduction: Daily pre‐exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is associated with a small but statistically significant decrease in estimated glomerular filtration rate (eGFR). We assessed the renal safety of on‐demand PrEP with TDF/FTC in HIV‐1 uninfected men. Methods: We used data from the randomized double‐blind placebo‐controlled ANRS‐IPERGAY trial and its open‐label extension conducted between February 2012 and June 2016 among HIV‐uninfected MSM starting on‐demand PrEP. Using linear mixed model, we evaluated the mean eGFR decline from baseline over time and determined risks factors associated with eGFR decline during the study. Results: During the blind phase, with a median follow‐up of 9.4 months, the mean decline slope of eGFR from baseline was −0.88 and −1.53 mL/min/1.73 m[sup.2] per year in the placebo (n = 201) and the TDF/FTC group (n = 198) respectively, with a slope difference of 0.65 mL/min/1.73 m[sup.2] per year (p = 0.27). Including both phases, 389 participants started on‐demand TDF/FTC with a median follow‐up of 19.2 months and a mean decline of eGFR from baseline of −1.14 mL/min/1.73 m[sup.2] per year (p < 0.001). The slope of eGFR reduction was not significantly different in participants with baseline eGFR ≤ 90 mL/min/1.73 m[sup.2] (p = 0.44), age >40 years (p = 0.24) or hypertension (p = 0.21). There was a dose‐response relationship between recent tenofovir exposure and lower eGFR when considering the number of pills taken in the two months prior the visit (eGFR difference of −0.88 mL/min/1.73 m[sup.2] between >15 pills/month vs. ≤15 pills/month, p < 0.01) or plasma tenofovir concentrations at the visit (eGFR difference compared to ≤2 ng/mL: >2 to ≤10ng/mL: −0.98 mL/min/1.73 m[sup.2], >10 to ≤40ng/mL: −1.28 mL/min/1.73 m[sup.2], >40 ng/mL: −1.82 mL/min/1.73 m[sup.2], p < 0.001). Three participants discontinued TDF/FTC for eGFR < 60 mL/min/1.73 m[sup.2] during the OLE phase. No case of Fanconi syndrome was reported. Conclusions: The renal safety of on‐demand PrEP with TDF/FTC was good. The overall reduction and intermittent exposure to TDF/FTC may explain this good renal safety., Introduction Pre‐exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) – emtricitabine (FTC) raises a lot of expectations to hamper HIV epidemic due to its high effectiveness to prevent HIV acquisition [...]

Background The impact of different therapeutic classes of drugs in antiretroviral therapy (ART) regimens on the CD4/CD8 ratio is not well documented in people treated for HIV. The objective of this study was to analyze the long-term effect of exposure to integrase strand transfer inhibitor (INSTI) on CD4/CD8 ratio compared with nonnucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) among ART-treated persons with HIV (PWH). Methods Data from the Quebec HIV Cohort collected from 31 August 2017 were used. Our analysis included all patients in the cohort who received a first or subsequent ART regimen composed of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and a third active drug of a different class (NNRTI, PI, or INSTI) for at least 16 weeks. Marginal structural Cox models were constructed to estimate the effect of different therapeutic classes on the CD4/CD8 ratio outcome. Results Among the 3907 eligible patients, 972 (24.9%), 1996 (51.1%), and 939 (24.0%) were exposed to an ART regimen whose third active agent was an NNRTI, PI, or INSTI, respectively. The total follow-up time was 13 640.24 person-years. The weighted hazard ratio for the association between the third active class and CD4/CD8 ratio ≥1 was.56 (95% confidence interval [CI]:.48–.65) for patients exposed to NNRTI + 2 NRTIs and.41 (95% CI:.35–.47) for those exposed to PI + 2 NRTIs, compared with those exposed INSTI + 2 NRTIs. Conclusions For people treated for HIV, INSTI-based ART appears to be associated with a higher CD4/CD8 ratio than NNRTI and PI-based ART. [ABSTRACT FROM AUTHOR]

We report that people with human immunodeficiency virus (HIV) diagnosed with coronary artery atherosclerotic plaques display higher levels of HIV DNA compared with those without atherosclerotic plaques. In a multivariable prediction model that included 27 traditional and HIV-related risk factors, measures of HIV DNA were among the most important predictors of atherosclerotic plaque formation. [ABSTRACT FROM AUTHOR]

: Introduction: Women living with HIV (WLHIV) experience stigma and elevated exposure to violence in comparison with HIV‐negative women. We examined the mediating role of experiencing recent violence in the relationship between stigma and depression among WLHIV in Canada. Methods: We conducted a cohort study with WLHIV in three Canadian provinces. Recent violence was assessed through self‐reported experiences of control, physical, sexual or verbal abuse in the past three months. At Time 1 (2013‐2015) three forms of stigma were assessed (HIV‐related, racial, gender) and at Time 2 (2015‐2017) only HIV‐related stigma was assessed. We conducted structural equation modelling (SEM) using the maximum likelihood estimation method with Time 1 data to identify direct and indirect effects of gender discrimination, racial discrimination and HIV‐related stigma on depression via recent violence. We then conducted mixed effects regression and SEM using Time 1 and Time 2 data to examine associations between HIV‐related stigma, recent violence and depression. Results: At Time 1 (n = 1296), the direct path from HIV‐related stigma (direct effect: β = 0.200, p < 0.001; indirect effect: β = 0.014, p < 0.05) to depression was significant; recent violence accounted for 6.5% of the total effect. Gender discrimination had a significant direct and indirect effect on depression (direct effect: β = 0.167, p < 0.001; indirect effect: β = 0.050, p < 0.001); recent violence explained 23.15% of the total effect. Including Time 1 and Time 2 data (n = 1161), mixed‐effects regression results indicate a positive relationship over time between HIV‐related stigma and depression (Acoef: 0.04, 95% CI: 0.03, 0.06, p < 0.001), and recent violence and depression (Acoef: 1.95, 95% CI: 0.29, 4.42, p < 0.05), controlling for socio‐demographics. There was a significant interaction between HIV‐related stigma and recent violence with depression (Acoef: 0.04, 95% CI: 0.01, 0.07, p < 0.05). SEM analyses reveal that HIV‐related stigma had a significant direct and indirect effect on depression over time (direct effect: β = 0.178, p < 0.001; indirect effect: β = 0.040, p < 0.001); recent violence experiences accounted for 51% of the total effect. Conclusions: Our findings suggest that HIV‐related stigma is associated with increased experiences of recent violence, and both stigma and violence are associated with increased depression among WLHIV in Canada. There is an urgent need for trauma‐informed stigma interventions to address stigma, discrimination and violence., Introduction Gender‐based violence (GBV) disproportionately impacts and compromises the wellbeing of women and girls across the world. A global participatory survey among women living with HIV (WLHIV) found that 89% [...]

Human cytomegalovirus (CMV) infection drives the expansion and differentiation of natural killer (NK) cells with adaptive-like features. We investigated whether age and time on antiretroviral therapy (ART) influenced adaptive NK cell frequency and functionality. Flow cytometry was used to evaluate the frequency of adaptive and conventional NK cells in 229 CMV+ individuals of whom 170 were people living with HIV (PLWH). The frequency of these NK cell populations producing CD107a, CCL4, IFN-γ or TNF-α was determined following a 6-h antibody dependent (AD) stimulation. Though ART duration and age were correlated, longer time on ART was associated with a reduced frequency of adaptive NK cells. In general, the frequency and functionality of NK cells following AD stimulation did not differ significantly between treated CMV+PLWH and CMV+HIV- persons, suggesting that HIV infection, per se, did not compromise AD NK cell function. AD activation of adaptive NK cells from CMV+PLWH induced lower frequencies of IFN-γ or TNF-α secreting cells in older persons, when compared with younger persons. [ABSTRACT FROM AUTHOR]

: Introduction: Guidelines regarding antiretroviral therapy (ART) initiation in HIV infection have varied over time, with the 2015 World Health Organization recommendation suggesting ART initiation at the time of diagnosis regardless of CD4 T‐cell counts. Herein, we investigated the influence of socio‐demographic and clinical factors in addition to time trends on early ART initiation among participants of the Montreal Primary HIV Infection Study. Methods: The Montreal Primary HIV Infection Study is a prospective cohort established in three community medical centres (CMCs) and two university medical centres (UMCs). Recently diagnosed HIV‐infected adults were categorized as receiving early (vs. delayed) ART if ART was initiated within 180 days of the baseline visit. Associations between early ART initiation and socio‐demographic, socio‐economic and behavioural information were examined. Independent associations of factors linked with early ART initiation were determined using multivariable binary logistic regression analysis. Results: A total of 348 participants had a documented date of HIV acquisition of Conclusions: Early ART initiation during primary HIV infection was associated with diminished biological prognostic factors and calendar time mirroring evolution of treatment guidelines. In addition, socio‐economic factors such as having a paid employment, contribute to early ART initiation in the context of universal access to care in Canada., Introduction Human immunodeficiency virus (HIV) affects over 36.7 million people worldwide. Nearly, half of those infected with HIV remain untreated, increasing their risks for acquired immune deficiency syndrome (AIDS), onward [...]