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Background: Despite successful antiretroviral therapy (ART), frequencies and immunological functions of memory CCR6 + Th17-polarised CD4 + T-cells are not fully restored in people with HIV (PWH). Moreover, long-lived Th17 cells contribute to HIV persistence under ART. However, the molecular mechanisms underlying these observations remain understudied., Methods: mRNA-sequencing was performed using Illumina technology on freshly FACS-sorted memory CCR6 + CD4 + T-cells from successfully ART-treated (ST), elite controllers (EC), and uninfected donors (HD). Gene expression validation was performed by RT-PCR, flow cytometry, and in vitro functional assays., Findings: Decreased Th17 cell frequencies in STs and ECs versus HDs coincided with reduced Th17-lineage cytokine production in vitro. Accordingly, the RORγt/RORC2 repressor NR1D1 was upregulated, while the RORγt/RORC2 inducer Semaphorin 4D was decreased in memory CCR6 + T-cells of STs and ECs versus HDs. The presence of HIV-DNA in memory CCR6 + T-cells of ST and EC corresponded with the downregulation of HIV restriction factors (SERINC3, KLF3, and RNF125) and HIV inhibitors (tetraspanins), along with increased expression of the HIV-dependency factor MRE11, indicative of higher susceptibility/permissiveness to HIV-1 infection. Furthermore, markers of DNA damage/modification were elevated in memory CCR6 + T-cells of STs and ECs versus HDs, in line with their increased activation (CD38/HLA-DR), senescence/exhaustion phenotype (CTLA-4/PD-1/CD57) and their decreased expression of proliferation marker Ki-67., Interpretation: These results reveal new molecular mechanisms of Th17 cell deficit in ST and EC PWH despite a successful control of HIV-1 replication. This knowledge points to potential therapeutic interventions to limit HIV-1 infection and restore frequencies, effector functions, and senescence/exhaustion in Th17 cells., Funding: This study was funded by the Canadian Institutes of Health Research (CIHR, operating grant MOP 142294, and the Canadian HIV Cure Enterprise [CanCURE 2.0] Team Grant HB2 164064), and in part, by the Réseau SIDA et maladies infectieuses du Fonds de recherche du Québec-Santé (FRQ-S)., Competing Interests: Declaration of interests We have no competing interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

While antiretroviral therapy (ART) has revolutionized the management of human immunodeficiency virus (HIV) and has enabled people living with HIV (PLWH) to achieve near-normal life expectancies, an HIV cure remains elusive due to the presence of HIV reservoirs. Furthermore, compared with individuals in the general population, PLWH support a higher burden of multimorbidity, including pulmonary diseases of both an infectious and non-infection nature, which may be a consequence of the formation of HIV reservoirs. Their gut, lymph nodes, brain, testes and lungs constitute important anatomic sites for the reservoirs. While CD4+ T cells, and particularly memory CD4+ T cells, are the best characterized cellular HIV reservoirs, tissue resident macrophages (TRM) and alveolar macrophages (AM) also harbor HIV infection. AM are the most abundant cells in bronchoalveolar (BAL) fluid in healthy conditions, and act as sentinels in the alveolar space by patrolling and clearing debris, microbes and surfactant recycling. Long-lived tissue-resident AM of embryonic origin have the capacity of self-renewal without replenishment from peripheral monocytes. As in other tissues, close cell-cell contacts in lungs also provide a milieu conducive for cell-to-cell spread of HIV infection and establishment of reservoirs. As lungs are in constant exposure to antigens from the external environment, this situation contributes to pro-inflammatory phenotype rendering pulmonary immune cells exhausted and senescent-an environment facilitating HIV persistence. Factors such as tobacco and e-cigarette smoking, lung microbiome dysbiosis and respiratory coinfections further drive antigenic stimulation and HIV replication. HIV replication, in turn, contributes to ongoing inflammation and clonal expansion. Herein, the potential role of AM in HIV persistence is discussed. Furthermore, their contribution towards pulmonary inflammation and immune dysregulation, which may in turn render PLWH susceptible to chronic lung disease, despite ART, is explored. Finally, strategies to eliminate HIV-infected AM are discussed.

Background: Socioeconomic status (SES) is a driver of health disparities and chronic diseases. People with HIV (PWH) are at risk for chronic liver diseases. We evaluated the association between low SES and hepatic outcomes in PWH., Methods: We included PWH from a prospective cohort. SES was assessed by the Pampalon material and social deprivation index to classify the cohort into quintiles of deprivation. Multivariable linear regression was used to investigate associations of material and social deprivation with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) as markers of hepatic fibrosis and steatosis, respectively. Incidence of outcomes was evaluated through survival analysis., Results: Among the 804 PWH included, 45% and 72% were living in areas of the highest material and social deprivation, respectively. Materially deprived PWH were more frequently female and of non-white ethnicity and had higher prevalence of metabolic comorbidities. After adjustments, material deprivation correlated with increased LSM (β = 1.86, 95% CI 0.53-3.17) but not with CAP (β = 6.47, 95% CI -5.55-18.49). Patients were observed for a median follow-up of 3.8 years. Incidence of liver-related events was higher in most materially deprived compared to most privileged PWH (hazard ratio 3.03, 95% CI 1.03-8.92), while there was no difference in extrahepatic outcomes or all-cause mortality. Social deprivation showed no association with either LSM or clinical outcomes., Conclusions: Living in materially deprived neighbourhoods as a proxy for lower SES, is associated with LSM and liver-related events in PWH. Future strategies should explore mechanisms underlying these relationships and whether enhanced material security improves hepatic outcomes., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Cannabis-based medicines (CBMs) could help reduce systemic inflammation in people with HIV (PWH). In a prospective, randomized pilot study we enrolled participants from August 2021-April 2022 with HIV, aged ≥18 and on antiretroviral therapy and randomly assigned them to cannabidiol (CBD) ± Δ9-tetrahydrocannabinol (THC) capsules for 12 weeks with the primary objective being to assess safety and tolerability. Here we report on timeliness to study initiation, enrolment, compliance and retention rates. The target sample size was not reached. Two hundred and five individuals were approached, and 10 consented and were randomized; the rest refused (reasons: cannabis-related stigma/discomfort; too many study visits/insufficient time; unwillingness to undergo a "washout period" for three weeks) or were not eligible. The age of those randomized was 58 years (IQR 55-62); 80% were male. Only three met all criteria (30% enrolment compliance); seven were enrolled with minor protocol deviations. Compliance was excellent (100%). Eight (80%) participants completed the study; two (20%) were withdrawn for safety reasons (transaminitis and aggravation of pre-existing anemia). Time to study initiation and recruitment were the most challenging aspects. Ongoing work is required to reduce stigma related to CBMs. Future studies should find a balance between the requirements for safety monitoring and frequency of study visits.

Chronic HIV infection is associated with accelerated coronary artery disease (CAD) due to chronic inflammation. The expanded endocannabinoid system (eCBome) and gut microbiota modulate each other and are key regulators of cardiovascular functions and inflammation. We herein investigated the interplay between plasma eCBome mediators and gut microbiota in people with HIV (PWH) and/or subclinical CAD versus HIV-uninfected individuals. CAD was determined by coronary computed tomography (CT) angiography performed on all participants. Plasma eCBome mediator and fecal microbiota composition were assessed by tandem mass spectrometry and 16S rDNA sequencing, respectively. HIV infection was associated with perturbed plasma eCBome mediators characterized by an inverse relationship between anandamide and N -acyl-ethanolamines (NAEs) versus 2-AG and 2-monoacylglycerols (MAGs). Plasma triglyceride levels were positively associated with MAGs. Several fecal bacterial taxa were altered in HIV-CAD+ versus controls and correlated with plasma eCBome mediators. CAD-associated taxonomic alterations in fecal bacterial taxa were not found in PWH., Competing Interests: We have no competing interest to declare., (© 2024 The Author(s).)

Chemotherapy-induced peripheral neuropathy (CIPN) remains a clinical challenge for up to 80% of breast cancer survivors. In an open-label study, participants underwent three interventions: standard care (duloxetine) for 1 month (Phase 1), oral cannabidiol (CBD) for 2 months (Phase 2), and CBD plus multi-modal exercise (MME) for another 2 months (Phase 3). Clinical outcomes and gut microbiota composition were assessed at baseline and after each phase. We present the case of a 52-year-old female with a history of triple-negative breast cancer in remission for over five years presenting with CIPN. She showed decreased monocyte counts, c-reactive protein, and systemic inflammatory index after each phase. Duloxetine provided moderate benefits and intolerable side effects (hyperhidrosis). She experienced the best improvement and least side effects with the combined (CBD plus MME) phase. Noteworthy were clinically meaningful improvements in CIPN symptoms, quality of life (QoL), and perceived physical function, as well as improvements in pain, mobility, hand/finger dexterity, and upper and lower body strength. CBD and MME altered gut microbiota, showing enrichment of genera that produce short-chain fatty acids. CBD and MME may improve CIPN symptoms, QoL, and physical function through anti-inflammatory and neuroprotective effects in cancer survivors suffering from long-standing CIPN.

Background: Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) suffer from a high burden of pulmonary diseases, even after accounting for their smoking status. Cytotoxic CD8 T-cells are likely implicated in this phenomenon and may act as a double-edged sword. While being essential in viral infection control, their hyperactivation can also contribute to lung mucosal tissue damage. The effects of HIV and smoking on pulmonary mucosal CD8 T-cell dynamics has been a neglected area of research, which we address herein., Methods: Bronchoalveolar lavage (BAL) fluid were obtained from ART-treated PLWH (median duration of supressed viral load: 9 years; smokers: n = 14; non-smokers: n = 21) and HIV-uninfected controls (smokers: n = 11; non-smokers: n = 20) without any respiratory symptoms or active infection. Lymphocytes were isolated and CD8 T-cell subsets and homing markers were characterized by multiparametric flow cytometry., Results: Both smoking and HIV infection were independently associated with a significant increase in frequencies of total pulmonary mucosal CD8 T-cell. BAL CD8 T-cells were primarily CD69 + expressing CD103 and/or CD49a, at least one of the two granzymes (GzmA/GzmB), and little Perforin. Higher expression levels of CD103, CD69, and GzmB were observed in smokers versus non-smokers. The ex vivo phenotype of GzmA + and GzmB + cells revealed increased expression of CD103 and CXCR6 in smokers, while PLWH displayed elevated levels of CX3CR1 compared to controls., Conclusion: Smoking and HIV could promote cytotoxic CD8 T-cell retention in small airways through different mechanisms. Smoking likely increases recruitment and retention of GzmB + CD8 Trm via CXCR6 and CD103. Heightened CX3CR1 expression could be associated with CD8 non-Trm recruitment from the periphery in PLWH., (© 2024. The Author(s).)

People living with HIV (PLWH) can exhibit impaired immune responses to vaccines. Accumulating evidence indicates that PLWH, particularly those receiving antiretroviral therapy, mount strong antibody responses to COVID-19 vaccines, but fewer studies have examined cellular immune responses to the vaccinations. Here, we used an activation-induced marker (AIM) assay to quantify SARS-CoV-2 spike-specific CD4+ and CD8+ T cells generated by two and three doses of COVID-19 vaccines in 50 PLWH receiving antiretroviral therapy, compared to 87 control participants without HIV. In a subset of PLWH, T-cell responses were also assessed after post-vaccine breakthrough infections and/or receipt of a fourth vaccine dose. All participants remained SARS-CoV-2 infection-naive until at least one month after their third vaccine dose. SARS-CoV-2 infection was determined by seroconversion to a Nucleocapsid (N) antigen, which occurred in 21 PLWH and 38 control participants after the third vaccine dose. Multivariable regression analyses were used to investigate the relationships between sociodemographic, health- and vaccine-related variables, vaccine-induced T-cell responses, and breakthrough infection risk. We observed that a third vaccine dose boosted spike-specific CD4+ and CD8+ T-cell frequencies significantly above those measured after the second dose (all p < 0.0001). Median T-cell frequencies did not differ between PLWH and controls after the second dose ( p > 0.1), but CD8+ T-cell responses were modestly lower in PLWH after the third dose ( p = 0.02), an observation that remained significant after adjusting for sociodemographic, health- and vaccine-related variables ( p = 0.045). In PLWH who experienced a breakthrough infection, median T-cell frequencies increased even higher than those observed after three vaccine doses ( p < 0.03), and CD8+ T-cell responses in this group remained higher even after a fourth vaccine dose ( p = 0.03). In multivariable analyses, the only factor associated with an increased breakthrough infection risk was younger age, which is consistent with the rapid increase in SARS-CoV-2 seropositivity that was seen among younger adults in Canada after the initial appearance of the Omicron variant. These results indicate that PLWH receiving antiretroviral therapy mount strong T-cell responses to COVID-19 vaccines that can be enhanced by booster doses or breakthrough infection.

COVID-19 breakthrough infection (BTI) can occur despite vaccination. Using a multi-centre, prospective, observational Canadian cohort of people with HIV (PWH) receiving ≥2 COVID-19 vaccines, we compared the SARS-CoV-2 spike (S) and receptor-binding domain (RBD)-specific IgG levels 3 and 6 months post second dose, as well as 1 month post third dose, in PWH with and without BTI. BTI was defined as positivity based on self-report measures (data up to last study visit) or IgG data (up to 1 month post dose 3). The self-report measures were based on their symptoms and either a positive PCR or rapid antigen test. The analysis was restricted to persons without previous COVID-19 infection. Persons without BTI remained COVID-19-naïve until ≥3 months following the third dose. Of 289 participants, 92 developed BTI (31.5 infections per 100 person-years). The median days between last vaccination and BTI was 128 (IQR 67, 176), with the most cases occurring between the third and fourth dose (n = 59), corresponding to the Omicron wave. In analyses adjusted for age, sex, race, multimorbidity, hypertension, chronic kidney disease, diabetes and obesity, a lower IgG S/RBD (log10 BAU/mL) at 1 month post dose 3 was significantly associated with BTI, suggesting that a lower IgG level at this time point may predict BTI in this cohort of PWH.

Introduction: Growth differentiation factor 15 (GDF-15) was originally described as a stress-induced cytokine, and a biomarker of aging and cardiovascular diseases. We hypothesized that circulating GDF-15 would be associated with COVID-19 disease severity. Herein, we explored this hypothesis in a large cohort of COVID-19 patients., Methods: Blood samples were collected from 926 COVID-19 adult patients and from 285 hospitalized controls from the Biobanque Québécoise de la COVID-19 (BQC19). COVID-19 severity was graded according to the WHO criteria. SOMAscan proteomics assay was performed on 50µL of plasma. ELISA were performed on 46 selected participants with left-over plasma to validate differences in plasma GDF-15 levels. Statistical analyses were conducted using GraphPad Prism 9.0 and SPSS. P values < 0.01 were considered significant., Results: Proteomics showed that plasma GDF-15 levels were higher in COVID-19 patients compared to hospitalized controls. GDF-15 levels increased with COVID-19 severity. COVID-19 patients presenting with comorbidities including diabetes, cancer, chronic obstructive pulmonary disease (COPD) and cardiovascular disease had higher GDF-15 levels. ELISA revealed significant elevation of GDF-15 until 30 days after hospitalization. Plasma GDF-15 elevation was correlated with older age. Moreover, GDF-15 levels correlated with pro-inflammatory cytokine interleukin-6 (IL-6) and inflammation marker C-reactive protein (CRP) as well as soluble levels of its putative receptor CD48. No association was established between anti-SARS-CoV-2 IgG levels and plasma GDF-15 levels., Conclusions: This study confirms GDF-15 as a biomarker for COVID-19 severity. Clinical evaluation of GDF-15 levels could assist identification of persons at high-risk of progressing to severe disease, thus improving patient care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Bu, Royston, Mabanga, Berini, Tremblay, Lebouché, Cox, Costiniuk, Durand, Isnard and Routy.)

The numbers of organ donors in Canada and the USA fall short of increasing demand, resulting in increased morbidity, poor health outcomes, higher medical costs and death of many individuals waitlisted for transplantation. In the US, since 2013 when the US HIV Organ Policy Equity (HOPE) Act lifted the ban on organ donation between people living with HIV, the option of using organs from People with HIV became a reality. In Canada, HIV diagnosis was an exclusion criterion to organ donation until 2017, when permission was granted if requirements for 'exceptional distribution' could be met. Still, donation of organs from people with HIV poses challenges. Herein, we overview policies involving donors with HIV in Canada in order to inform healthcare providers, researchers and the community. We also advocate for the need to reassess these policies, highlight educational needs and engage interest in advancing research to inform policy reforms.

Introduction: The Last Gift study at the University of California San Diego (UCSD), United States enrolls terminally ill people with HIV (PWH) in HIV cure research., Methods: From 2017 to 2022, we conducted surveys with Last Gift participants and their next-of-kin/loved ones to evaluate willingness to participate in different types of HIV cure research at the end of life (EOL). We analyzed willingness data descriptively., Results: We surveyed 17 Last Gift participants and 17 next-of-kin/loved ones. More than half of Last Gift participants ( n  = 10; 58.8%) expressed willingness to participate in studies involving totally new treatments or approaches ('first-in-human' studies), a combination of different approaches, the use of unique antibodies, proteins or molecules, or therapeutic vaccines. Under one-quarter of Last Gift participants ( n  = 4; 23.5%) expressed willingness to participate in research involving interventions that may shorten their life expectancy to benefit medical research. Most Last Gift participants and their next-of-kin/loved ones also expressed high acceptance for various types of donations and biopsies at the EOL (e.g. hair donations and skin, lymph node or gut biopsies)., Discussion: Knowing whether people would be willing to participate in different types of EOL HIV cure research can help inform the design of future innovative studies. As a research community, we have a duty to design studies with adequate safeguards to preserve the public trust in research and honor PWH's important gift to humanity., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Few studies have examined preventative behaviour practices with respect to COVID-19 among people living with HIV (human immunodeficiency virus). Using a cross-sectional survey from a Canadian Institutes of Health Research Canadian HIV Trials Network study (CTN 328) of people living with HIV on vaccine immunogenicity, we examined the relationships between participant characteristics and behavioural practices intended to prevent COVID-19 infection. Participants living in four Canadian urban centers were enrolled between April 2021-January 2022, at which time they responded to a questionnaire on preventative behaviour practices. Questionnaire and clinical data were combined to explore relationships between preventive behaviours and (1) known COVID-19 infection pre-enrolment, (2) multimorbidity, (3) developing symptomatic COVID-19 infection, and (4) developing symptomatic COVID-19 infection during the Omicron wave. Among 375 participants, 49 had COVID-19 infection pre-enrolment and 88 post-enrolment. The proportion of participants reporting always engaging in preventative behaviours included 87% masking, 79% physical distancing, 70% limiting social gatherings, 65% limiting contact with at-risk individuals, 33% self-isolating due to symptoms, and 26% self-quarantining after possible exposure. Participants with known COVID-19 infection pre-enrolment were more likely to self-quarantine after possible exposure although asymptomatic (65.0% vs 23.4%, p < 0.001; Chi-square test). Participants with multiple comorbidities more likely endorsed physical distancing (85.7% vs 75.5%, p = 0.044; Chi-square test), although this was not significant in logistic regression analysis adjusted for age, sex, race, number of household members, number of bedrooms/bathrooms in the household per person, influenza immunization, and working in close physical proximity to others. Overall, participants reported frequent practice of preventative behaviours., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Many people living with HIV (PLWH) use cannabis for medicinal reasons. Patients' knowledge of the tetrahydrocannabinol (THC) and cannabidiol (CBD) concentrations of the cannabis products they use may be important in helping patients achieve symptom relief while guarding against potential risks of cannabis use. However, no studies have examined cannabinoid concentration knowledge among PLWH., Method: PLWH (N = 29; 76% men, mean age 47 years) reporting cannabis use for both medicinal and nonmedicinal reasons completed daily surveys over 14 days assessing cannabis products used, knowledge of cannabinoid concentrations of cannabis products used, cannabis use motives (medicinal, nonmedicinal, both), and positive and negative cannabis-related consequences. Across the 361 cannabis use days captured on the daily surveys, at least some knowledge of cannabinoid concentrations was reported on an average of 43.1% (for THC) and 26.6% (for CBD) of the days., Results: Generalized linear mixed models revealed that participants were more likely to report knowing THC and CBD concentrations on days when they used non-flower forms of cannabis relative to days when they used cannabis flower only. Participants who used cannabis for medicinal reasons on a greater proportion of days had greater knowledge of cannabinoid concentration overall across days. Further, greater overall knowledge of cannabinoid concentrations was associated with fewer reported negative cannabis-related consequences., Conclusions: Findings suggest that among PLWH, knowledge of cannabinoid concentrations may be higher when using non-flower cannabis products and among those reporting primarily medicinal cannabis use. Moreover, knowledge of cannabinoid concentration may protect against negative cannabis-related consequences in this population., (© 2023. International Society of Behavioral Medicine.)

Introduction: People living with HIV (PLWH) and/or who inject drugs may experience lower vaccine effectiveness (VE) against SARS-CoV-2 infection., Methods: A validated algorithm was applied to population-based, linked administrative datasets in the British Columbia COVID-19 Cohort (BCC19C) to ascertain HIV status and create a population of PLWH and matched HIV-negative individuals. The study population was limited to individuals who received an RT-PCR laboratory test for SARS-CoV-2 between 15 December 2020 and 21 November 2021 in BC, Canada. Any history of injection drug use (IDU) was ascertained using a validated administrative algorithm. We used a test-negative study design (modified case-control analysis) and multivariable logistic regression to estimate adjusted VE by HIV status and history of IDU., Results: Our analysis included 2700 PLWH and a matched population of 375,043 HIV-negative individuals, among whom there were 351 and 103,049 SARS-CoV-2 cases, respectively. The proportion of people with IDU history was much higher among PLWH compared to HIV-negative individuals (40.7% vs. 4.3%). Overall VE during the first 6 months after second dose was lower among PLWH with IDU history (65.8%, 95% CI = 43.5-79.3) than PLWH with no IDU history (80.3%, 95% CI = 62.7-89.6), and VE was particularly low at 4-6 months (42.4%, 95% CI = -17.8 to 71.8 with IDU history vs. 64.0%; 95% CI = 15.7-84.7 without), although confidence intervals were wide. In contrast, overall VE was 88.6% (95% CI = 88.2-89.0) in the matched HIV-negative population with no history of IDU and remained relatively high at 4-6 months after second dose (84.6%, 95% CI = 83.8-85.4). Despite different patterns of vaccine protection by HIV status and IDU history, peak estimates were similar (≥88%) across all populations., Conclusions: PLWH with a history of IDU may experience lower VE against COVID-19 infection, although findings were limited by a small sample size. The lower VE at 4-6 months may have implications for booster dose prioritization for PLWH and people who inject drugs. The immunocompromising effect of HIV, substance use and/or co-occurring comorbidities may partly explain these findings., (© 2023 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Objective: To examine the risk of hospitalization within 14 days of COVID-19 diagnosis among people living with HIV (PLWH) and HIV-negative individuals who had laboratory-confirmed SARS-CoV-2 infection., Methods: We used Cox proportional hazard models to compare the relative risk of hospitalization in PLWH and HIV-negative individuals. Then, we used propensity score weighting to examine the influence of sociodemographic factors and comorbid conditions on risk of hospitalization. These models were further stratified by vaccination status and pandemic period (pre-Omicron: December 15, 2020, to November 21, 2021; Omicron: November 22, 2021, to October 31, 2022)., Results: The crude hazard ratio (HR) for risk of hospitalization in PLWH was 2.44 (95% confidence interval [CI]: 2.04-2.94). In propensity score-weighted models that included all covariates, the relative risk of hospitalization was substantially attenuated in the overall analyses (adjusted HR [aHR]: 1.03; 95% CI: 0.85-1.25), in vaccinated (aHR 1.00; 95% CI: 0.69-1.45), inadequately vaccinated (aHR: 1.04; 95% CI: 0.76-1.41) and unvaccinated individuals (aHR: 1.15; 95% CI: 0.84-1.56)., Conclusion: PLWH had about two times the risk of COVID-19 hospitalization than HIV-negative individuals in crude analyses which attenuated in propensity score-weighted models. This suggests that the risk differential can be explained by sociodemographic factors and history of comorbidity, underscoring the need to address social and comorbid vulnerabilities (e.g., injecting drugs) that were more prominent among PLWH., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Objectives: Many vaccines require higher/additional doses or adjuvants to provide adequate protection for people with HIV (PWH). Here, we compare coronavirus disease 2019 (COVID-19) vaccine-induced antibody neutralization capacity in PWH vs. HIV-negative individuals following two vaccine doses., Design: In Canadian prospective observational cohorts, including a multicentre study of PWH receiving at least two COVID-19 vaccinations (mRNA or ChAdOx1-S), and a parallel study of HIV-negative controls (Stop the Spread Ottawa Cohort), we measured vaccine-induced neutralization capacity 3 months post dose 2 (±1 month)., Methods: COVID-19 neutralization efficiency was measured by calculating the half maximal inhibitory dilution (ID50) using a high-throughput protein-based neutralization assay for Ancestral (Wuhan), Delta and Omicron (BA.1) spike variants. Univariable and multivariable quantile regression were used to compare COVID-19-specific antibody neutralization capacity by HIV status., Results: Neutralization assays were performed on 256 PWH and 256 controls based on specimen availability at the timepoint of interest, having received two vaccines and known date of vaccination. There was a significant interaction between HIV status and previous COVID-19 infection status in median ID50. There were no differences in median ID50 for HIV+ vs. HIV-negative persons without past COVID-19 infection. For participants with past COVID-19 infection, median ICD50 was significantly higher in controls than in PWH for ancestral SARS-CoV-2 and Omicron variants, with a trend for the Delta variant in the same direction., Conclusion: Vaccine-induced SARS-CoV-2 neutralization capacity was similar between PWH vs. HIV-negative persons without past COVID-19 infection, demonstrating favourable humoral-mediated immunogenicity. Both HIV+ and HIV-negative persons demonstrated hybrid immunity., Trial Registration: clinicaltrials.gov NCT04894448., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

HIV persists in tissues during antiretroviral therapy (ART), but the relative contribution of different anatomical compartments to the viral reservoir in humans remains unknown. We performed an extensive characterization of HIV reservoirs in two men who donated their bodies to HIV cure research and who had been on suppressive ART for years. HIV DNA is detected in all tissues, with large variations across anatomical compartments and between participants. Intact HIV genomes represent 2% and 25% of all proviruses in the two participants and are mainly detected in secondary lymphoid organs, with the spleen and mediastinal lymph nodes harboring intact viral genomes in both individuals. Multiple copies of identical HIV genomes are found in all tissues, indicating that clonal expansions are common in anatomical sites. The majority (>85%) of these expanded clones are shared across multiple tissues. These findings suggest that infected cells expand, migrate, and possibly circulate between anatomical sites., Competing Interests: Declaration of interests The authors have declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

People living with HIV (PLWH) display altered gut epithelium that allows for the translocation of microbial products, contributing to systemic immune activation. Although there are numerous studies which examine the gut bacterial microbiome in PLWH, few studies describing the fungal microbiome, or the mycobiome, have been reported. Like the gut bacterial microbiome, the fungal microbiome and its by-products play a role in maintaining the body's homeostasis and modulating immune function. We conducted a prospective study to assess the effects of oral terbinafine, an antifungal agent widely used against onychomycosis, on gut permeability and microbiome composition in ART-treated PLWH (trial registration: ChiCTR2100043617). Twenty participants completed all follow-up visits. During terbinafine treatment, the levels of the intestinal fatty acid binding protein (I-FABP) significantly increased, and the levels of interleukin-6 (IL-6) significantly decreased, from baseline to week 12. Both markers subsequently returned to pre-treatment levels after terbinafine discontinuation. After terbinafine treatment, the abundance of fungi decreased significantly, while the abundance of the bacteria did not change. After terbinafine discontinuation, the abundance of fungi returned to the levels observed pre-treatment. Moreover, terbinafine treatment induced only minor changes in the composition of the gut bacterial and fungal microbiome. In summary, oral terbinafine decreases fungal microbiome abundance while only slightly influencing gut permeability and microbial translocation in ART-treated PLWH. This study's findings should be validated in larger and more diverse studies of ART-treated PLWH; our estimates of effect size can be used to inform optimal sample sizes for future studies.

Introduction: Advanced chronic liver disease (ACLD) is a major cause of death for people with HIV (PWH). While viral hepatitis coinfections are largely responsible for this trend, metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging concern for PWH. We aimed to assess the contribution of MASLD to incident ACLD in PWH., Methods and Analysis: This multicentre prospective observational cohort study will enrol 968 consecutive HIV monoinfected patients from four Canadian sites, excluding subjects with alcohol abuse, liver disease other than MASLD, or ACLD at baseline. Participants will be followed annually for 4 years by clinical evaluation, questionnaires, laboratory testing and Fibroscan to measure liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). The primary outcome will be incidence of ACLD, defined as LSM>10 kPa, by MASLD status, defined as CAP≥285 dB/m with at least one metabolic abnormality, and to develop a score to classify PWH according to their risk of ACLD. Secondary outcomes will include health-related quality of life (HRQoL) and healthcare resource usage. Kaplan-Meier survival method and Cox proportional hazards regression will calculate the incidence and predictors of ACLD, respectively. Propensity score methods and marginal structural models will account for time-varying exposures. We will split the cohort into a training set (to develop the risk score) and a validation set (for validation of the score). HRQoL scores and healthcare resource usage will be compared by MASLD status using generalised linear mixed effects model., Ethics and Dissemination: This protocol has been approved by the ethics committees of all participating institutions. Written informed consent will be obtained from all study participants. The results of this study will be shared through scientific publications and public presentations to advocate for the inclusion of PWH in clinical trials of MASLD-targeted therapies and case-finding of ACLD in PWH., Competing Interests: Competing interests: BL has acted as a speaker and advisory board member for ViiV, Gilead and Merck, and received research funding from ViiV, Merck and Gilead. CTC has received research funding from Merck, Gilead and Tilray, speaker honorarium from Gilead and consultant fees from ViiV Healthcare and Moderna. She has received funding to attend conferences from Gilead and ViiV Healthcare, and cannabinoids from Tilray for use in a clinical trial. SLW has served on advisory board, and spoken at CME event for Merck, Gilead, Viiv, and has received research funds from ViiV, Gilead and Merck. JC has received funding for investigator-initiated research from ViiV Healthcare and remuneration for advisory work from Gilead Canada and ViiV Healthcare. MCMM has served on advisory boards and spoken at CME events for Merck, Gilead and Viiv, and has received research funds from Viiv. GS has acted as speaker for Merck, Gilead, Abbvie, NovoNordisk, Pfizer, served as an advisory board member for Pfizer, Merck, NovoNordisk, Gilead and Intercept and has received unrestricted research funding from Theratecnologies. FC, SS, DK, LRB, WE, EEMM, CP, KM, NP, NK, AdP, J-PR, MBK have no conflict of interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Currently, there is no cure for human immunodeficiency virus type 1 (HIV-1) infection. However, combined antiretroviral therapy (cART) aids in viral latency and prevents the progression of HIV-1 infection into acquired immunodeficiency syndrome (AIDS). cART has extended many lives, but people living with HIV-1 (PLWH) face lifelong ailments such as HIV-associated neurocognitive disorders (HAND) that range from asymptomatic HAND to HIV-1-associated dementia. HAND has been attributed to chronic inflammation and low-level infection within the central nervous system (CNS) caused by proinflammatory cytokines and viral products. These molecules are shuttled into the CNS within extracellular vesicles (EVs), lipid bound nanoparticles, and are released from cells as a form of intercellular communication. This study investigates the impact of cannabidiol (CBD), as a promising and potential therapeutic for HAND patients, and a similar synthetic molecule, HU308, on the EVs released from HIV-1-infected myeloid cells as well as HIV-1-infected 3D neurospheres. The data shows that both CBD and HU308 decrease non-coding and coding viral RNA (TAR and env ) as well as proinflammatory cytokines as IL -1β and TNF -α mRNA. This decrease in viral RNA occurs in in vitro differentiated primary macrophages, in EVs released from HIV-1-infected cells monocytes, and infected neurospheres. Furthermore, a 3D neurosphere model shows an overall decrease in proinflammatory mRNA with HU308. Finally, using a humanized mouse model of HIV-1 infection, plasma viral RNA was shown to significantly decrease with HU308 alone and was most effective in combination with cART, even when compared to the typical cART treatment. Overall, CBD or HU308 may be a viable option to decrease EV release and associated cytokines which would dampen the virus spread and may be used in effective treatment of HAND in combination with cART.

Understanding the roots of Covid-19 vaccine hesitancy in at-risk groups, such as persons living with HIV (PLWH), is of utmost importance. We developed a modified Vaccine Hesitancy Scale (VHS) questionnaire using items from the National Advisory Committee on Immunization Acceptability Matrix. To examine factors associated with receiving COVID-19 vaccine and the link between vaccine attitudes and beliefs with vaccine behavior, PLWH were recruited via social media and community-based organizations (February-May 2022). Descriptive statistics were used to summarize results. Total VHS score was generated by adding Likert scale scores and linear regression models used to compare results between participants who received or did not receive COVID-19 vaccines. Logistic regression models were used to identify factors associated with vaccine uptake. A total of 246 PLWH indicated whether they received a COVID-19 vaccine. 89% received ≥ 1 dose. Mean total VHS(SD) for persons having received ≥ 1 COVID-19 vaccine was 17.8(6.2) vs. 35.4(9.4) for participants not having received any COVID-19 vaccine. Persons who received ≥ 1 dose were significantly older than those who had not received any (48.4 ± 13.8 vs. 34.0 ± 7.7 years, p < 0.0001). The majority of participants considered COVID-19 vaccination important for their health(81.3%) and the health of others(84.4%). Multivariate logistic regression revealed the odds of taking ≥ 1dose were increased 2.4-fold [95% CI 1.6, 3.5] with each increase in age of 10 years (p < 0.0001). Sex and ethnicity were not different between groups. In conclusion, PLWH accept COVID-19 vaccines for both altruistic and individual reasons. With evolving recommendations and increasing numbers of booster vaccines, we must re-examine the needs of PLWH regularly., (© 2023. The Author(s).)

Chronic HIV infection is characterized by persistent inflammation despite antiretroviral therapy (ART). Cannabinoids may help reduce systemic inflammation in people with HIV (PWH). To assess the effects of oral cannabinoids during HIV, ten PWH on ART were randomized ( n = 5/group) to increasing doses of oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (2.5:2.5-15:15 mg/day) capsules or CBD-only (200-800 mg/day) capsules for 12 weeks. Blood specimens were collected prospectively 7-21 days prior to treatment initiation and at weeks 0 to 14. Plasma cytokine levels were determined via Luminex and ELISA. Immune cell subsets were characterized by flow cytometry. HIV DNA/RNA were measured in circulating CD4 T-cells and sperm by ultra-sensitive qPCR. Results from both arms were combined for statistical analysis. Plasma levels of IFN-γ, IL-1β, sTNFRII, and REG-3α were significantly reduced at the end of treatment ( p ˂ 0.05). A significant decrease in frequencies of PD1+ memory CD4 T-cells, CD73+ regulatory CD4 T-cells, and M-DC8+ intermediate monocytes was also observed ( p ˂ 0.05), along with a transient decrease in CD28-CD57+ senescent CD4 and CD8 T-cells. Ki-67+ CD4 T-cells, CCR2+ non-classical monocytes, and myeloid dendritic cells increased over time ( p ˂ 0.05). There were no significant changes in other inflammatory markers or HIV DNA/RNA levels. These findings can guide future large clinical trials investigating cannabinoid anti-inflammatory properties.

Introduction: Although current antiretroviral therapy allows most people with HIV (PWH) to experience normal longevity with a good quality of life, an HIV cure remains elusive due to HIV reservoir formation within deep tissues. An HIV cure remains highly desirable to the community of PWH. This study reports on the perceived risks and benefits of participation in the Last Gift study, a study aimed at characterizing HIV reservoirs via post-mortem autopsy, among PWH at the end of life (EOL) and their next-of-kin (NOK)/loved ones., Methods: Last Gift participants (PWH with a terminal illness and/or near the end of life) and their NOK/loved ones were surveyed for perceptions of risks, benefits, and meaning for participation in the Last Gift study., Results: The average age of the 17 Last Gift participants was 66.6 years, 3 were females, 1 person identified as Hispanic, and 15 as Caucasian. The average age of the 17 NOK/loved ones was 56.7 years, and relationships to Last Gift participants included partner/spouse, sibling, friend, child, parent, grandparent, and nephew. The only perceived personal risk of the Last Gift among participants was the blood draws (3/17). NOK/loved ones perceived the following risks: blood draws (2/17), physical pain (3/17), worry that something bad will happen (2/17), and unpleasant side effects (1/17). Participants in Last Gift and NOK/loved ones indicated the study had various positive social effects. For both participants and NOK/loved ones, the most frequent perceived personal benefit of the Last Gift was the satisfaction of supporting HIV cure research., Discussion: Participants perceived minimal personal and societal risks and valued the altruistic benefits of participating in the Last Gift study. Last Gift participants and NOK/loved ones were cautious about possible personal risks of EOL HIV cure research but still viewed that the emotional, psychological and societal benefits of participation outweighed potential risks., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

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., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

This study examined the feasibility of using ecological momentary assessment (EMA) to disentangle medicinal cannabis use (MCU) from recreational cannabis use (RCU) among people living HIV (PLWH). Over a 14-day period, PLWH (N = 29) who engaged in both MCU and RCU completed a smartphone-based survey before and after every cannabis use event assessing general motivation for cannabis use (MCU-only, RCU-only, or mixed MCU/RCU), cannabis use behavior, and several antecedents and outcomes of cannabis use. A total of 739 pre-cannabis surveys were completed; 590 (80%) of the prompted post-cannabis surveys were completed. Motives for cannabis use were reported as MCU-only on 24%, RCU-only on 30%, and mixed MCU/RCU on 46% of pre-cannabis surveys. Mixed effects models examined within-person differences across MCU-only, RCU-only, and mixed MCU/RCU events. Results showed that relative to RCU-only events, MCU-only events were more likely to involve symptom management and drug substitution motives, physical and sleep-related symptoms, solitary cannabis use, and use of cannabis oils and sprays; MCU-only events were less likely to involve relaxation, happiness, and wellness motives, cannabis flower use, and positive cannabis consequences. Differences between mixed MCU/RCU and RCU-only events were similar, except that mixed MCU/RCU events were additionally associated with stress reduction motives and symptoms of anxiety and depression. Findings support the feasibility of partially disentangling MCU and RCU behavior among PLWH who engage in concurrent MCU and RCU. This study highlights the need for more EMA studies isolating MCU from RCU to inform ongoing changes to cannabis policies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

People living with HIV (PLWH) may be at risk for poor immunogenicity to certain vaccines, including the ability to develop immunological memory. Here, we assessed T-cell immunogenicity following three SARS-CoV-2 vaccine doses in PLWH versus uninfected controls. Blood was collected from 38 PLWH on antiretroviral therapy and 24 age-matched HIV-negative controls, pre-vaccination and after 1st/2nd/3rd dose of SARS-CoV-2 vaccines, without prior SARS-CoV-2 infection. Flow cytometry was used to assess ex vivo T-cell immunophenotypes and intracellular Tumor necrosis factor (TNF)-α/interferon(IFN)-γ/interleukin(IL)-2 following SARS-CoV-2-Spike-peptide stimulation. Comparisons were made using Wilcoxon signed-rank test for paired variables and Mann-Whitney for unpaired. In PLWH, Spike-specific CD4 T-cell frequencies plateaued post-2nd dose, with no significant differences in polyfunctional SARS-CoV-2-specific T-cell proportions between PLWH and uninfected controls post-3rd dose. PLWH had higher frequencies of TNFα+CD4 T-cells and lower frequencies of IFNγ+CD8 T-cells than seronegative participants post-3rd dose. Regardless of HIV status, an increase in naive, regulatory, and PD1+ T-cell frequencies was observed post-3rd dose. In summary, two doses of SARS-CoV-2 vaccine induced a robust T-cell immune response in PLWH, which was maintained after the 3rd dose, with no significant differences in polyfunctional SARS-CoV-2-specific T-cell proportions between PLWH and uninfected controls post-3rd dose.

Objectives: We estimated the effectiveness of COVID-19 vaccines against laboratory-confirmed SARS-CoV-2 infection among people living with HIV (PLWH) and compared the estimates with a matched HIV-negative cohort., Methods: We used the British Columbia COVID-19 Cohort, a population-based data platform, which integrates COVID-19 data on SARS-CoV-2 tests, laboratory-confirmed cases, and immunizations with provincial health services data. The vaccine effectiveness (VE) was estimated with a test-negative design using the multivariable logistic regression., Results: The adjusted VE against SARS-CoV-2 infection was 71.1% (39.7, 86.1%) 7-59 days after two doses, rising to 89.3% (72.2, 95.9%) between 60 and 89 days. VE was preserved 4-6 months after the receipt of two doses, after which noticeable waning was observed (51.3% [4.8, 75.0%]). In the matched HIV-negative cohort (n = 375,043), VE peaked at 91.4% (90.9, 91.8%) 7-59 days after two doses and was sustained for up to 4 months, after which evidence of waning was observed, dropping to 84.2% (83.4, 85.0%) between 4 and 6 months., Conclusion: The receipt of two COVID-19 vaccine doses was effective against SARS-CoV-2 infection among PLWH pre-Omicron. VE estimates appeared to peak later in PLWH than in the matched HIV-negative cohort and the degree of waning was relatively quicker in PLWH; however, peak estimates were comparable in both populations., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Chronic cytomegalovirus (CMV) infection is very frequent in people living with HIV (PLWH). High anti-CMV IgG titres, which may be linked to transient CMV replication, have been associated with earlier mortality, CD8 T-cell expansion, lower CD4/CD8 ratio and increased T-cell senescence. We previously showed that anti-CMV IgG titres correlated with gut permeability in PLWH on antiretroviral therapy (ART), which was associated with microbial translocation, systemic inflammation and non-infectious/non-AIDS comorbidities. Letermovir, a novel anti-CMV drug with a good safety profile, was recently approved for anti-CMV prophylaxis in allogeneic haematopoietic stem cell transplant recipients. A drastic and selective reduction of both low-grade replication and clinically significant CMV infections, combined with an improved immune reconstitution have been reported. In vitro , letermovir prevented CMV-induced epithelial disruption in intestinal tissues. Based on these findings, we aim to assess whether letermovir could inhibit CMV subclinical replication in CMV-seropositive PLWH receiving ART and, in turn, decrease CMV-associated gut damage and inflammation., Method and Analysis: We will conduct a multi-centre, open-label, randomised, controlled clinical trial, including a total of 60 CMV-seropositive ART-treated PLWH for at least 3 years, with a viral load <50 copies/mL and CD4 + count >400 cells/µL. Forty participants will be randomised to receive letermovir for 14 weeks and 20 participants will receive standard of care (ART) alone. Plasma, pheripheral blood mononuclear cells (PBMCs), and stool samples will be collected. Colon biopsies will be collected in an optional substudy. We will assess the effect of letermovir on gut damage, microbial translocation, inflammation and HIV reservoir size., Ethics and Dissemination: The study was approved by Health Canada and the Research Ethics Boards of the McGill University Health Centre (MUHC-REB, protocol number: MP37-2022-8295). Results will be made available through publications in open access peer-reviewed journals and through the CIHR/CTN website., Trial Registration Number: NCT05362916., Competing Interests: Competing interests: LR is a post-doctoral fellow supported by the Swiss National Science Foundation (SNSF) and the CTN/CIHR. SI is a post-doctoral fellow from the Fonds de recherche du Quebec en santé, and from the CIHR/CTN. J-PR is the holder of the Louis Lowenstein Chair in Hematology and Oncology, McGill University. J-PR has performed contract research and/or served on Advisory Boards for Gilead Sciences Canada, Merck Canada, Abbvie, ViiV Healthcare, Bristol Myers Squibb, Janssen. NC has received research funding from EMD Serono and has served on the Advisory Board of Gilead Sciences Canada. AdP is a senior Clinical Research Scholar supported by Fonds de la recherche Quebec -Santé (FRQ-S). BL is a senior Clinical Research Scholar supported by FRQ-S and received consultancy fees and/or honoraria from Gilead, Merck, and ViiV, and obtained research funds from Gilead, Merck, and ViiV, and support to attend educational conferences from Viiv Healthcare and Gilead. CTC is supported by a Fonds de recherche du Québec-Santé (FRQS) Junior 2 career award and has received consultancy fees and/or honoraria from Gilead and ViiV, and obtained research funds from Gilead, Merck, and ViiV, and support to attend educational conferences from Viiv Healthcare and Gilead. NK reports research funding from Gilead Sciences, advisory fees from Gilead Sciences, ViiV Healthcare, Merck and Abbvie, and speaker fees from Gilead Sciences, Abbvie and Merck, all outside of the submitted work. NK is supported by a career award from the Fonds de Recherche Québec – Santé (FRQ-S; Junior 1). CTC is the Pfizer/Université de Montréal Chair on HIV translational research and has received consultancy fees and honoraria from Gilead, Merck, GSK, Astra-Zeneca, Medicago, Sanofi. This study is supported in part (study drug in-kind) by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Many vaccines require higher/additional doses or adjuvants to provide adequate protection for people with HIV (PWH). Our objective was to compare COVID-19 vaccine immunogenicity in PWH to HIV-negative individuals., Design: In a Canadian multi-center prospective, observational cohort of PWH receiving at least two COVID-19 vaccinations, we measured vaccine-induced immunity at 3 and 6 months post 2nd and 1-month post 3rd doses., Methods: The primary outcome was the percentage of PWH mounting vaccine-induced immunity [co-positivity for anti-IgG against SARS-CoV2 Spike(S) and receptor-binding domain proteins] 6 months post 2nd dose. Univariable and multivariable logistic regressions were used to compare COVID-19-specific immune responses between groups and within subgroups., Results: Data from 294 PWH and 267 controls were analyzed. Immunogenicity was achieved in over 90% at each time point in both groups. The proportions of participants achieving comparable anti-receptor-binding domain levels were similar between the group at each time point. Anti-S IgG levels were similar by group at month 3 post 2nd dose and 1-month post 3rd dose. A lower proportion of PWH vs. controls maintained vaccine-induced anti-S IgG immunity 6 months post 2nd dose [92% vs. 99%; odds ratio: 0.14 (95% confidence interval: 0.03, 0.80; P = 0.027)]. In multivariable analyses, neither age, immune non-response, multimorbidity, sex, vaccine type, or timing between doses were associated with reduced IgG response., Conclusion: Vaccine-induced IgG was elicited in the vast majority of PWH and was overall similar between groups. A slightly lower proportion of PWH vs. controls maintained vaccine-induced anti-S IgG immunity 6 months post 2nd dose demonstrating the importance of timely boosting in this population., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: With anti-inflammatory properties, cannabinoids may be a potential strategy to reduce immune activation in people living with HIV (PLWH) but more information on their safety and tolerability is needed., Methods: We conducted an open-label interventional pilot study at the McGill University Health Centre in Montreal, Canada. PLWH were randomized to oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (THC 2.5 mg/CBD 2.5 mg) or CBD-only capsules (CBD 200 mg). Individuals titrated doses as tolerated to a maximum daily dose THC 15 mg/CBD 15 mg or 800 mg CBD, respectively, for 12 weeks. The primary outcome was the percentage of participants without any significant toxicity based on the WHO toxicity scale (Grades 0-2 scores)., Results: Out of ten individuals, eight completed the study. Two from the CBD-only arm were withdrawn for safety concerns: phlebotomy aggravating pre-existing anemia and severe hepatitis on 800 mg CBD with newly discovered pancreatic adenocarcinoma, respectively. Seven did not have any significant toxicity. Cannabinoids did not alter hematology/biochemistry profiles. CD4 count, CD4/CD8 ratio, and HIV suppression remained stable. Most adverse effects were mild-moderate., Conclusions: In PLWH, cannabinoids seem generally safe and well-tolerated, though larger studies are needed. Screening for occult liver pathology should be performed and hepatic enzymes monitored, especially with high CBD doses.

Objective: People with HIV were underrepresented in coronavirus disease 2019 (COVID-19) vaccine clinical trials. We estimated vaccine effectiveness (VE) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection for the BNT162b2, mRNA-1273, and ChAdOx1 vaccines among a population-based cohort of people with HIV in Ontario, Canada., Design: Test-negative design., Methods: We identified people with HIV aged ≥19 years who were tested for SARS-CoV-2 by RT-PCR between December 14, 2020 (first availability of COVID-19 vaccines) and November 21, 2021 (pre-Omicron circulation). Outcomes included any infection, symptomatic infection, and COVID-19-related hospitalization/death. We compared the odds of vaccination between test-positive cases and test-negative controls using multivariable logistic regression with adjustment for age, sex, region, calendar time, SARS-CoV-2 test histories, influenza vaccination, comorbidities, and neighborhood-level socio-economic status. VE was derived as (1 - adjusted odds ratio) × 100%., Results: Among 21 023 adults living with HIV, there were 801 (8.3%) test-positive cases and 8,879 (91.7%) test-negative controls. 20.1% cases and 47.8% of controls received ≥1 COVID-19 vaccine dose; among two-dose recipients, 93.4% received ≥1 mRNA dose. Two-dose VE ≥7 days before specimen collection was 82% (95% confidence interval [CI] = 74-87%) against any infection, 94% (95% CI = 82-98%) against symptomatic infection, and 97% (95% CI = 85-100%) against hospitalization/death. Against any infection, VE declined from 86% (95% CI = 77-92%) within 7-59 days after the second dose to 66% (95% CI = -15-90%) after ≥180 days; we did not observe evidence of waning protection for other outcomes., Conclusion: Two doses of COVID-19 vaccine offered substantial protection against symptomatic illness and hospitalization/death in people with HIV prior to the emergence of the Omicron variant. Our findings do not support a broad conclusion that COVID-19 VE is lower among people with HIV in populations that, for the most part, are attending HIV care, taking antiretroviral medication, and are virally suppressed., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Pulmonary dysbiosis may predispose people living with HIV (PLWH) to chronic lung disease. Herein, we assessed whether intrapulmonary HIV reservoir size and immune disruption are associated with reduced bacterial lung diversity in PLWH. Bacterial DNA was extracted and PCR-amplified from cell-free bronchoalveolar lavage (BAL) fluid from 28 PLWH and 9 HIV-negative controls. Amplicon sequence variant (ASV) relative abundances and taxonomic identities were analyzed using joint species distribution modeling. HIV-DNA was quantified from blood and pulmonary CD4+ T-cells using ultra-sensitive qPCR. Immunophenotyping of BAL T-cells was performed using flow cytometry. Lung microbiome diversity was lower in smokers than non-smokers and microbiome composition was more variable in PLWH than HIV-negative individuals. Frequencies of effector memory BAL CD4+ and CD8+ T-cells positively correlated with abundance of several bacterial families while frequencies of BAL activated CD4+ T-cells negatively correlated with abundance of most lung bacterial families. Higher HIV-DNA levels in blood, but not in BAL, as well as frequencies of senescent CD4+ T-cells were associated with reduced bacterial diversity. These findings suggest that HIV infection may weaken the relationship between the lung microbiome and smoking status. Viral reservoir and immune activation levels may impact the lung microbiome, predisposing PLWH to pulmonary comorbidities., Competing Interests: The authors declare no conflict of interest.

Background: Canadians seeking medical cannabis (MC) may encounter difficulties in finding a healthcare provider (HCP) who authorizes their access to it. Barriers that HCPs face in authorizing MC are unclear. The objectives of this study were to evaluate HCP opinions, knowledge, comfort, and practice in MC prescribing and counseling on recreational cannabis use, and whether the COVID-19 pandemic affected MC prescribing practices., Methods: Eligible participants included HCPs (e.g., attending physicians, nurses, pharmacists) in Canada. A questionnaire evaluating their knowledge, comfort, and practice in medical and recreational cannabis was designed based on instruments developed in previous studies. Between April 13 th -December 13 th 2021, ninety-one healthcare associations were asked to distribute the survey to their members, and an advertisement was placed in the online Canadian Medical Association Journal. Descriptive statistics were used to analyze the results., Results: Twenty-four organizations agreed to disseminate the survey and 70 individuals completed it. Of respondents, 71% were attending physicians or medical residents, while the remainder were nurses, pharmacists or other HCPs. Almost none (6%) received training in MC in professional school but 60% did receive other training (e.g., workshops, conferences). Over half (57%) received more questions regarding MC since recreational cannabis was legalized, and 82% reported having patients who use MC. However, 56% felt uncomfortable or ambivalent regarding their knowledge of MC, and 27% were unfamiliar with the requirements for obtaining MC in Canada. The most common symptoms for recommending MC were pain and nausea, whereas the most common conditions for recommending it were cancer and intractable pain. The strongest barrier to authorizing MC was uncertainty in safe and effective dosage and routes of administration. The strongest barrier to recommending or authorizing MC was the lack of research evidence demonstrating its safety and efficacy. During the pandemic, many respondents reported that a greater number of their patients used cannabis to relieve anxiety and depression., Conclusions: Our results suggest that HCPs across Canada who responded to our survey are unfamiliar with topics related to MC. The strongest barriers appear to be lack of clinical research, and uncertainty in safe and effective MC administration. Increasing research, training, and knowledge may help HCPs feel more equipped to make informed treatment/prescribing decisions, which may help to improve access to MC., (© 2022. The Author(s).)

Background: The role of remdesivir in the treatment of hospitalized patients with COVID-19 remains ill-defined. We conducted a cost-effectiveness analysis alongside the Canadian Treatments for COVID-19 (CATCO) open-label, randomized clinical trial evaluating remdesivir., Methods: Patients with COVID-19 in Canadian hospitals from Aug. 14, 2020, to Apr. 1, 2021, were randomly assigned to receive remdesivir plus usual care versus usual care alone. Taking a public health care payer's perspective, we collected in-hospital outcomes and health care resource utilization alongside estimated unit costs in 2020 Canadian dollars over a time horizon from randomization to hospital discharge or death. Data from 1281 adults admitted to 52 hospitals in 6 Canadian provinces were analyzed., Results: The total mean cost per patient was $37 918 (standard deviation [SD] $42 413; 95% confidence interval [CI] $34 617 to $41 220) for patients randomly assigned to the remdesivir group and $38 026 (SD $46 021; 95% CI $34 480 to $41 573) for patients receiving usual care (incremental cost -$108 [95% CI -$4953 to $4737], p > 0.9). The difference in proportions of in-hospital deaths between remdesivir and usual care groups was -3.9% (18.7% v. 22.6%, 95% CI -8.3% to 1.0%, p = 0.09). The difference in proportions of incident invasive mechanical ventilation events between groups was -7.0% (8.0% v. 15.0%, 95% CI -10.6% to -3.4%, p = 0.006), whereas the difference in proportions of total mechanical ventilation events between groups was -5.7% (16.4% v. 22.1%, 95% CI -10.0% to -1.4%, p = 0.01). Remdesivir was the dominant intervention (but only marginally less costly, with mildly lower mortality) with an incalculable incremental cost effectiveness ratio; we report results of incremental costs and incremental effects separately. For willingness-to-pay thresholds of $0, $20 000, $50 000 and $100 000 per death averted, a strategy using remdesivir was cost-effective in 60%, 67%, 74% and 79% of simulations, respectively. The remdesivir costs were the fifth highest cost driver, offset by shorter lengths of stay and less mechanical ventilation., Interpretation: From a health care payer perspective, treating patients hospitalized with COVID-19 with remdesivir and usual care appears to be preferrable to treating with usual care alone, albeit with marginal incremental cost and small clinical effects. The added cost of remdesivir was offset by shorter lengths of stay in the intensive care unit and less need for ventilation., Study Registration: ClinicalTrials. gov, no. NCT04330690., Competing Interests: Competing interests: Robert Fowler is the H. Barrie Fairley Professor of Critical Care Medicine at the University Health Network and the University of Toronto Interdepartmental Division of Critical Care Medicine. Robert Fowler declares a Canadian Institutes of Health Research (CIHR) operating grant. John Conly declares grants from the CIHR, Pfizer and the World Health Organization (WHO). He declares a peer-reviewed research grant on acute and primary care preparedness for COVID-19 in Alberta, Canada; he was a primary local investigator for the STRIVE Staphylococcus aureus vaccine randomized controlled trial in vertebral spinal surgery with instrumentation for which all funding was provided only to the University of Calgary; he was a co-investigator on a WHO-funded study using integrated human factors and ethnography approaches to identify and scale innovative infection prevention and control (IPC) guidance implementation supports in primary care with a focus on low-resource settings and using drone aerial systems to deliver medical supplies and personal protective equipment to remote First Nations communities during the COVID-19 pandemic. John Conly also reports receiving accommodations and airfare from the Centers for Disease Control and Prevention to attend a meeting in 2019. He is a member and chair of the WHO Infection Prevention and Control Research and Development Expert Group for COVID-19 and a member of the WHO Health Emergencies Programme Ad-hoc COVID-19 IPC Guidance Development Group, both of which provide multidisciplinary advice to the WHO, for which no funding is received and from which no funding recommendations are made for any WHO contracts or grants. He is also a member of the Cochrane Acute Respiratory Infections Group. Darrell Tan is supported by a Tier 2 Canada Research Chair in HIV Prevention and STI Research. Ryan Zarychanski reports grants from the CIHR, the Peter Munk Cardiac Centre, the Thistledown Foundation and the National Institutes of Health. He is a WHO thrombostasis technical advisory member. Ryan Zarychanski is the recipient of the Lyonel G. Israels Research Chair in Hematology at the University of Manitoba. Todd Lee reports a CATCO operating grant from the CIHR as a co–principal investigator and a co-investigator. He reports various operating grants from the CIHR, a technical development grant from the Centre for Aging + Brain Health Innovation and research salary support from the Fonds de recherche du Québec — Santé. He is the co-owner of a company that is bringing Med-Safer to market. Srinivas Murthy is the Innovative Medicines Canada and Health Research Foundation Chair in Pandemic Preparedness Research. Srinivas Murthy reports a grants from the CIHR and Health Research Foundation and Innovative Medicines Canada., (© 2022 CMA Impact Inc. or its licensors.)

Nonalcoholic fatty liver disease (NAFLD), alcohol-induced liver disease (ALD), and viral hepatitis are the main causes of morbidity and mortality related to chronic liver diseases (CLDs) worldwide. New therapeutic approaches to prevent or reverse these liver disorders are thus emerging. Although their etiologies differ, these CLDs all have in common a significant dysregulation of liver metabolism that is closely linked to the perturbation of the hepatic endocannabinoid system (eCBS) and inflammatory pathways. Therefore, targeting the hepatic eCBS might have promising therapeutic potential to overcome CLDs. Experimental models of CLDs and observational studies in humans suggest that cannabis and its derivatives may exert hepatoprotective effects against CLDs through diverse pathways. However, these promising therapeutic benefits are not yet fully validated, as the few completed clinical trials on phytocannabinoids, which are thought to hold the most promising therapeutic potential (cannabidiol or tetrahydrocannabivarin), remained inconclusive. Therefore, expanding research on less studied phytocannabinoids and their derivatives, with a focus on their mode of action on liver metabolism, might provide promising advances in the development of new and original therapeutics for the management of CLDs, such as NAFLD, ALD, or even hepatitis C-induced liver disorders.

HIV cure research requires interrogating latent HIV reservoirs in deep tissues, which necessitates autopsies to avoid risks to participants. An HIV autopsy biobank would facilitate this research, but such research raises ethical issues and requires participant engagement. This study explores the willingness to participate in HIV cure research at the end of life. Participants include Canadians with HIV [people with HIV (PWHIV)] aged 55 years or older. Following a mixed-method study design, all participants completed a phone or online survey, and a subset of participants participated in in-depth phone or videoconference interviews. We produced descriptive statistics of quantitative data and a thematic analysis of qualitative data. Barriers and facilitators were categorized under domains of the Theoretical Domains Framework. From April 2020 to August 2021, 37 participants completed the survey (mean age = 69.9 years old; mean duration of HIV infection = 28.5 years), including 15 interviewed participants. About three quarters of participants indicated being willing to participate in hypothetical medical studies toward the end of life ( n  = 30; 81.1%), in HIV biobanking ( n  = 30; 81.1%), and in a research autopsy ( n  = 28; 75.7%) to advance HIV cure research, mainly for altruistic benefits. The main perceived risks had to do with physical pain and confidentiality. Barriers and facilitators were distributed across five domains: social/professional role and identity, environmental context and resources, social influences, beliefs about consequences, and capabilities. Participants wanted more information about study objectives and procedures, possible accommodations with their last will, and rationale for studies or financial interests funding studies. Our results indicate that older PWHIV would be willing to participate in HIV cure research toward the end of life, HIV biobanking, and research autopsy. However, a dialogue should be initiated to inform participants thoroughly about HIV cure studies, address concerns, and accommodate their needs and preferences. Additional work is required, likely through increased community engagement, to address educational needs.

Objectives: Besides CD4 regulatory T-cells (Tregs), immunosuppressor FoxP3 + CD8 T-cells are emerging as an important subset of Tregs, which contribute to immune dysfunction and disease progression in HIV infection. However, FoxP3 + CD8 T-cell dynamics in acute HIV infection and following early antiretroviral therapy (ART) initiation remain understudied., Methods: Subsets of FoxP3 + CD8 T-cells were characterized both prospectively and cross-sectionally in PBMCs from untreated acute (n=26) and chronic (n=10) HIV-infected individuals, early ART-treated in acute infection (n=10, median of ART initiation: 5.5 months post-infection), ART-treated in chronic infection (n=10), elite controllers (n=18), and HIV-uninfected controls (n=21)., Results: Acute and chronic infection were associated with increased total, effector memory, and terminally differentiated FoxP3 + CD8 T-cells, while early ART normalized only the frequencies of total FoxP3 + CD8 T-cells. We observed an increase in FoxP3 + CD8 T-cell immune activation (HLADR + /CD38 + ), senescence (CD57 + /CD28 - ), and PD-1 expression during acute and chronic infection, which were not normalized by early ART. FoxP3 + CD8 T-cells in untreated participants expressed higher levels of immunosuppressive LAP(TGF-β1) and CD39 than uninfected controls, whereas early ART did not affect their expression. The expression of gut-homing markers CCR9 and Integrin-β7 by total FoxP3 + CD8 T-cells and CD39 + and LAP(TGF-β1) + FoxP3 + CD8 T-cells increased in untreated individuals and remained higher than in uninfected controls despite early ART. Elite controllers share most of the FoxP3 + CD8 T-cell characteristics in uninfected individuals., Conclusions: Although early ART normalized total FoxP3 + CD8 T-cells frequencies, it did not affect the persistent elevation of the gut-homing potential of CD39 + and LAP(TGF-β1) + FoxP3 + CD8 T-cell, which may contribute to immune dysfunction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yero, Shi, Routy, Tremblay, Durand, Costiniuk and Jenabian.)

Introduction: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection of immunocompromised hosts with significant morbidity and mortality. The current standard of care, trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of 15-20 mg/kg/day, is associated with serious adverse drug events (ADE) in 20%-60% of patients. ADEs include hypersensitivity reactions, drug-induced liver injury, cytopenias and renal failure, all of which can be treatment limiting. In a recent meta-analysis of observational studies, reduced dose TMP-SMX for the treatment of PJP was associated with fewer ADEs, without increased mortality., Methods and Analysis: A phase III randomised, placebo-controlled, trial to directly compare the efficacy and safety of low-dose TMP-SMX (10 mg/kg/day of TMP) with the standard of care (15 mg/kg/day of TMP) among patients with PJP, for a composite primary outcome of change of treatment, new mechanical ventilation, or death. The trial will be undertaken at 16 Canadian hospitals. Data will be analysed as intention to treat. Primary and secondary outcomes will be compared using logistic regression adjusting for stratification and presented with 95% CI., Ethics and Dissemination: This study has been conditionally approved by the McGill University Health Centre; Ethics approval will be obtained from all participating centres. Results will be submitted for publication in a peer-reviewed journal., Trial Registration Number: NCT04851015., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We performed retrospective chart reviews and described the clinical characteristics, exposure risks, and disease severity of people living with HIV (PLWH) attending the Chronic Viral Illness Service (CVIS) in Montreal, Canada, who developed coronavirus disease 2019 (COVID-19) during September 2020-August 2021, coinciding with the second and third waves of the pandemic. A total of 61 PLWH with a positive COVID-19 polymerase chain reaction were identified, giving a COVID-19 prevalence of 5%. The most common exposure risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during waves two and three was having a family member/close contact with COVID-19 (36%). Similar to what we observed during the first wave, PLWH who acquired COVID-19 during waves two and three of the pandemic often worked or lived in long-term care residences or health care settings, putting them at risk. Five people (8%) were asymptomatic. Nearly all persons had mild disease on initial presentation and most had a full recovery. Two individuals were admitted to hospital with COVID-19, whereas three individuals acquired COVID-19 nosocomially. No individuals died due to COVID-19. Two individuals developed symptoms associated with long COVID-19 syndrome. Findings highlight the ongoing impact of the social determinants of health during the second and third waves of the pandemic in PLWH.

People living with HIV (PLWH) often have worse health outcomes compared to HIV-uninfected individuals. We characterized PLWH followed at a tertiary care clinic in Montreal who acquired COVID-19 and described their outcomes during the first wave of the pandemic. A retrospective chart review was performed for PLWH followed at the Chronic Viral Illness Service with a positive COVID-19 nasopharyngeal PCR or symptoms suggestive of COVID-19 between 1 March and 15 June 2020. Data on demographics, socioeconomic status, co-morbidities and severity of COVID-19 and outcomes were extracted. Of 1702 individuals, 32 (1.9%) had a positive COVID-19 test ( n  = 24) or symptoms suspicious for COVID-19 ( n  = 3). Median age was 52 years [IQR 40, 62]. Nearly all (97%) earned $34,999 Canadian dollars or less. Eleven (34%) individuals worked in long-term care (LTC) homes while 5 (6%) lived in LTC homes. Median CD4 count was 566 cells/mm 3 [347, 726] and six had detectable plasma HIV viral loads. Median duration of HIV was 17 years [7, 22] and 30 individuals had been prescribed antiretroviral therapy. Five persons were asymptomatic. Of symptomatic persons, 21 (12%), 1 (4%) and 3 (12%) individuals had mild, moderate and severe disease, respectively. Three individuals died with COVID-19. In one case, the cause of death was due to COVID-19, whereas in the other two cases, the individuals died with positive COVID-19 test results but the immediate cause of death is unclear. PLWH who tested positive for COVID-19 had low socioeconomic status and had employment or living conditions that put them at high risk. PLWH may be disproportionately impacted by the social determinants of health which predispose them to COVID-19.

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/mm 3 , though nadir CD4+ T-cell counts ranged as low as <10 cells/mm 3 . 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., (© 2022. The Author(s).)

Of the 37.9 million individuals infected with human immunodeficiency virus type 1 (HIV-1), approximately 50% exhibit HIV-associated neurocognitive disorders (HAND). We and others previously showed that HIV-1 viral RNAs, such as trans-activating response (TAR) RNA, are incorporated into extracellular vesicles (EVs) and elicit an inflammatory response in recipient naïve cells. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the primary cannabinoids present in cannabis, are effective in reducing inflammation. Studies show that cannabis use in people living with HIV-1 is associated with lower viral load, lower circulating CD16 + monocytes and high CD4 + T-cell counts, suggesting a potentially therapeutic application. Here, HIV-1 infected U1 monocytes and primary macrophages were used to assess the effects of CBD. Post-CBD treatment, EV concentrations were analyzed using nanoparticle tracking analysis. Changes in intracellular and EV-associated viral RNA were quantified using RT-qPCR, and changes in viral proteins, EV markers, and autophagy proteins were assessed by Western blot. Our data suggest that CBD significantly reduces the number of EVs released from infected cells and that this may be mediated by reducing viral transcription and autophagy activation. Therefore, CBD may exert a protective effect by alleviating the pathogenic effects of EVs in HIV-1 and CNS-related infections.