Monkeypox in Montréal: Epidemiology, Phylogenomics, and Public Health Response to a Large North American Outbreak.

BACKGROUND: Monkeypox, a viral zoonotic disease, is causing a global outbreak outside of endemic areas. OBJECTIVE: To characterize the outbreak of monkeypox in Montréal, the first large outbreak in North America. DESIGN: Epidemiologic and laboratory surveillance data and a phylogenomic analysis were used to describe and place the outbreak in a global context. SETTING: Montréal, Canada. PATIENTS: Probable or confirmed cases of monkeypox. MEASUREMENTS: Epidemiologic, clinical, and demographic data were aggregated. Whole-genome sequencing and phylogenetic analysis were performed for a set of outbreak sequences. The public health response and its evolution are described. RESULTS: Up to 18 October 2022, a total of 402 cases of monkeypox were reported mostly among men who have sex with men (MSM), most of which were suspected to be acquired through sexual contact. All monkeypox genomes nested within the B.1 lineage. Montréal Public Health worked closely with the affected communities to control the outbreak, becoming the first jurisdiction to offer 1 dose of the Modified Vaccinia Ankara-Bavarian Nordic vaccine as preexposure prophylaxis (PrEP) to those at risk in early June 2022. Two peaks of cases were seen in early June and July (43 and 44 cases per week, respectively) followed by a decline toward near resolution of the outbreak in October. Reasons for the biphasic peak are not fully elucidated but may represent the tempo of vaccination and/or several factors related to transmission dynamics and case ascertainment. LIMITATIONS: Clinical data are self-reported. Limited divergence among sequences limited genomic epidemiologic conclusions. CONCLUSION: A large outbreak of monkeypox occurred in Montréal, primarily among MSM. Successful control of the outbreak rested on early and sustained engagement with the affected communities and rapid offer of PrEP vaccination to at-risk persons. PRIMARY FUNDING SOURCE: None.

Safety and Tolerability of Oral Cannabinoids in People Living with HIV on Long-Term ART: A Randomized, Open-Label, Interventional Pilot Clinical Trial (CTNPT 028).

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.

Depression, diabetes and immigration status: a retrospective cohort study using the Canadian Longitudinal Study on Aging.

BACKGROUND: A bidirectional association between depression and diabetes exists, but has not been evaluated in the context of immigrant status. Given that social determinants of health differ between immigrants and nonimmigrants, we evaluated the association between diabetes and depression incidence, depression and diabetes incidence, and whether immigrant status modified this association, among immigrants and nonimmigrants in Canada. METHODS: We employed a retrospective cohort design using data from the Canadian Longitudinal Study on Aging Comprehensive cohort (baseline [2012-2015] and 3-year follow-up [2015-2018]). We defined participants as having diabetes if they self-reported it or if their glycated hemoglobin A1c level was 7% or more; we defined participants as having depression if their Center for Epidemiological Studies Depression score was 10 or higher or if they were currently undergoing depression treatment. We excluded those with baseline depression (Cohort 1) and baseline diabetes (Cohort 2) to evaluate the associations between diabetes and depression incidence, and between depression and diabetes incidence, respectively. We constructed logistic regression models with interaction by immigrant status. RESULTS: Cohort 1 (n = 20 723; mean age 62.7 yr, standard deviation [SD] 10.1 yr; 47.6% female) included 3766 (18.2%) immigrants. Among immigrants, 16.4% had diabetes, compared with 15.6% among nonimmigrants. Diabetes was associated with an increased risk of depression in nonimmigrants (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.08-1.49), but not in immigrants (adjusted OR 1.12, 95% CI 0.80-1.56). Younger age, female sex, weight change, poor sleep quality and pain increased depression risk. Cohort 2 (n = 22 054; mean age 62.1 yr, SD 10.1 yr; 52.2% female) included 3913 (17.7%) immigrants. Depression was associated with an increased risk of diabetes in both nonimmigrants (adjusted OR 1.39, 95% CI 1.16-1.68) and immigrants (adjusted OR 1.60, 95% CI 1.08-2.37). Younger age, male sex, waist circumference, weight change, hypertension and heart disease increased diabetes risk. INTERPRETATION: We found an overall bidirectional association between diabetes and depression that was not significantly modified by immigrant status. Screening for diabetes for people with depression and screening for depression for those with diabetes should be considered.

Chemsex and incidence of sexually transmitted infections among Canadian pre-exposure prophylaxis (PrEP) users in the l'Actuel PrEP Cohort (2013-2020).

OBJECTIVES: Use of illicit substances during sex (chemsex) may increase transmission of HIV and other STIs. Pre-exposure prophylaxis (PrEP) is highly effective at preventing HIV transmission, providing an important prevention tool for those who practise chemsex. However, it does not prevent acquisition of other STIs. We aim to examine the impact of chemsex on STI incidence among gay, bisexual and other men who have sex with men (gbMSM), and transgender women using PrEP in Montréal, Canada. METHODS: We linked baseline sociodemographic and behavioural data with follow-up STI testing from 2013 to 2020 among PrEP users in the l'Actuel PrEP Cohort (Canada). Focusing on the 24 months following PrEP initiation, we estimated the effect of chemsex reported at baseline on cumulative incidence of gonorrhoea and chlamydia using Kaplan-Meier curves and survival analyses. We investigated the role of polysubstance use and effect modification by sociodemographic factors. RESULTS: There were 2086 clients (2079 cisgender gbMSM, 3 transgender gbMSM, 4 transgender women) who initiated PrEP, contributing 1477 years of follow-up. There were no incident HIV infections among clients on PrEP. Controlling for sociodemographic confounders, clients reporting chemsex at baseline had a 32% higher hazard of gonorrhoea/chlamydia diagnosis (adjusted HR=1.32; 95% CI: 1.10 to 1.57), equivalent to a risk increase of 8.9 percentage points (95% CI: 8.5 to 9.4) at 12 months. The effect was greater for clients who reported polysubstance use (adjusted HR=1.51; 95% CI: 1.21 to 1.89). The strength of the effect of chemsex on STI incidence varied by age, education and income. CONCLUSION: Among PrEP users, chemsex at baseline was linked to increased incidence of gonorrhoea and chlamydia. This effect was stronger for people reporting multiple chemsex substances. The high STI incidence among gbMSM who report chemsex highlights the importance of PrEP for this population and the need for integrated services that address the complexities of sexualised substance use.

Characterization of people living with HIV in a Montreal-based tertiary care center with COVID-19 during the first wave of the pandemic.

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/mm3 [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.

Characteristics of new HIV diagnoses over 1995-2019: A clinic-based study in Montréal, Canada.

BACKGROUND: Characterization of populations at risk of acquiring HIV is required to inform the public health response to HIV. To identify potential changing needs in HIV prevention and care cascade, we aim to describe how the demographic profiles and exposure categories of newly diagnosed HIV positive individuals attending a large sexual health clinic in Montréal (Canada) evolved since the beginning of the antiretroviral therapy era in the mid-1990s. METHODS: Using diagnosis data from participants of the Clinique médicale l'Actuel cohort of HIV-positive patients, we examined the distribution of exposure categories (sexual orientation, sexual behaviours, injection drug use, being born in an HIV-endemic country) by gender and year of diagnosis. Time trends in mean age and in the proportion of patients with late (CD4 <350 cells/µL) or advanced stage (CD4 <200 cells/µL) of HIV infection at diagnosis were assessed through meta-regressions. RESULTS: A total of 2,612 patients diagnosed with HIV between January 1st, 1995 and December 31st, 2019 were included. Overall, mean age was 35 years (standard deviation: 10 years) and remained stable over time. The proportion of patients with advanced stage of HIV infection decreased from 16% in 1995 to 4% in 2019. Although men who have sex with men (MSM) consistently accounted for the highest proportion of new diagnoses (77%, 2,022/2,612 overall), their proportion decreased since 2013. There was also a concomitant decrease in the proportion of people who inject drugs, with none of the newly diagnosed participants reporting injection drug use since 2017, and an important increase in the proportion of patients born in an HIV-endemic country (24%, 7/29 in 2019), especially among women. Compared to patients from non-endemic countries, those from HIV-endemic countries were characterized by higher proportions of heterosexuals (88% vs 17%) and of women (52% vs 7%), and were twice likely to get diagnosed at an advanced stage of HIV infection (32% vs 15%). CONCLUSIONS: In absolute numbers, MSM continue to account for the largest exposure category. However, patients from HIV-endemic countries, who tend to be diagnosed at later stages of HIV infection, constitute an increasing proportion of newly diagnosed individuals. These persons could face distinct barriers to rapid diagnosis. Tailoring HIV testing strategies and other prevention interventions to the specific unmet prevention needs of these individuals is warranted.

Evolution of Antibodies to Native Trimeric Envelope and Their Fc-Dependent Functions in Untreated and Treated Primary HIV Infection.

People living with HIV (PLWH) develop both anti-envelope-specific antibodies, which bind the closed trimeric HIV envelope present on infected cells, and anti-gp120-specific antibodies, which bind gp120 monomers shed by infected cells and taken up by CD4 on uninfected bystander cells. Both antibodies have an Fc portion that binds to Fc receptors on several types of innate immune cells and stimulates them to develop antiviral functions. Among these Fc-dependent functions (FcDFs) are antibody-dependent (AD) cellular cytotoxicity (ADCC), AD cellular trogocytosis (ADCT), and AD phagocytosis (ADCP). In this study, we assessed the evolution of total immunoglobulin G (IgG), anti-gp120, and anti-envelope IgG antibodies and their FcDFs in plasma samples from antiretroviral therapy (ART)-naive subjects during early HIV infection (28 to 194 days postinfection [DPI]). We found that both the concentrations and FcDFs of anti-gp120 and anti-envelope antibodies increased with time in ART-naive PLWH. Although generated concurrently, anti-gp120-specific antibodies were 20.7-fold more abundant than anti-envelope-specific antibodies, both specificities being strongly correlated with each other and FcDFs. Among the FcDFs, only ADCP activity was inversely correlated with concurrent viral load. PLWH who started ART at >90 DPI showed higher anti-envelope-specific antibody levels and ADCT and ADCP activities than those starting ART at<90 DPI. However, in longitudinally collected samples, ART initiation at >90 DPI was accompanied by a faster decline in anti-envelope-specific antibody levels, which did not translate to a faster decline in FcDFs than for those starting ART at <90 DPI. IMPORTANCE Closed-conformation envelope is expressed on the surface of HIV-infected cells. Antibodies targeting this conformation and that support FcDFs have the potential to control HIV. This study tracked the timing of the appearance and evolution of antibodies to closed-conformation envelope, whose concentration increased over the first 6 months of infection. Antiretroviral therapy (ART) initiation blunts further increases in the concentration of these antibodies and their and FcDFs. However, antibodies to open-conformation envelope also increased with DPI until ART initiation. These antibodies target uninfected bystander cells, which may contribute to loss of uninfected CD4 cells and pathogenicity. This report presents, for the first time, the evolution of antibodies to closed-conformation envelope and their fate on ART. This information may be useful in making decisions on the timing of ART initiation in early HIV infection.

Influence of NKG2C Genotypes on HIV Susceptibility and Viral Load Set Point.

NKG2C is an activating NK cell receptor encoded by a gene having an unexpressed deletion variant. Cytomegalovirus (CMV) infection expands a population of NKG2C+ NK cells with adaptive-like properties. Previous reports found that carriage of the deleted NKG2C- variant was more frequent in people living with HIV (PLWH) than in HIV- controls unexposed to HIV. The frequency of NKG2C+ NK cells positively correlated with HIV viral load (VL) in some studies and negatively correlated with VL in others. Here, we investigated the link between NKG2C genotype and HIV susceptibility and VL set point in PLWH. NKG2C genotyping was performed on 434 PLWH and 157 HIV-exposed seronegative (HESN) subjects. Comparison of the distributions of the three possible NKG2C genotypes in these populations revealed that the frequencies of NKG2C+/+ and NKG2C+/- carriers did not differ significantly between PLWH and HESN subjects, while that of NKG2C-/- carriers was higher in PLWH than in HESN subjects, in which none were found (P = 0.03, χ2 test). We were unable to replicate that carriage of at least 1 NKG2C- allele was more frequent in PLWH. Information on the pretreatment VL set point was available for 160 NKG2C+/+, 83 NKG2C+/-, and 6 NKG2C-/- PLWH. HIV VL set points were similar between NKG2C genotypes. The frequency of NKG2C+ CD3- CD14- CD19- CD56dim NK cells and the mean fluorescence intensity (MFI) of NKG2C expression on NK cells were higher on cells from CMV+ PLWH who carried 2, versus 1, NKG2C+ alleles. We observed no correlations between VL set point and either the frequency or the MFI of NKG2C expression. IMPORTANCE We compared NKG2C allele and genotype distributions in subjects who remained HIV uninfected despite multiple HIV exposures (HESN subjects) with those in the group PLWH. This allowed us to determine whether NKG2C genotype influenced susceptibility to HIV infection. The absence of the NKG2C-/- genotype among HESN subjects but not PLWH suggested that carriage of this genotype was associated with HIV susceptibility. We calculated the VL set point in a subset of 252 NKG2C-genotyped PLWH. We observed no between-group differences in the VL set point in carriers of the three possible NKG2C genotypes. No significant correlations were seen between the frequency or MFI of NKG2C expression on NK cells and VL set point in cytomegalovirus-coinfected PLWH. These findings suggested that adaptive NK cells played no role in establishing the in VL set point, a parameter that is a predictor of the rate of treatment-naive HIV disease progression.

Pre-exposure Prophylaxis Uptake Among Men Who Have Sex With Men Who Used nPEP: A Longitudinal Analysis of Attendees at a Large Sexual Health Clinic in Montréal (Canada).

BACKGROUND: Reducing HIV transmission using pre-exposure prophylaxis (PrEP) requires focussing on individuals at high acquisition risk, such as men who have sex with men with a history of nonoccupational post-exposure prophylaxis (nPEP). This study aims to characterize longitudinal trends in PrEP uptake and its determinants among nPEP users in Montréal. METHODS: Eligible attendees at Clinique médicale l'Actuel were recruited prospectively starting in October 2000 (nPEP) and January 2013 (PrEP). Linking these cohorts, we characterized the nPEP-to-PrEP cascade, examined the determinants of PrEP uptake after nPEP consultation using a Cox proportional-hazard model, and assessed whether PrEP persistence differed by nPEP history using Kaplan-Meier curves. RESULTS: As of August 2019, 31% of 2682 nPEP cohort participants had 2 or more nPEP consultations. Subsequent PrEP consultations occurred among 36% of nPEP users, of which 17% sought nPEP again afterward. Among 2718 PrEP cohort participants, 46% reported previous nPEP use. Among nPEP users, those aged 25-49 years [hazard ratio (HR) = 1.3, 95% confidence interval (CI): 1.1 to 1.7], with more nPEP episodes (HR = 1.4, 95% CI: 1.3 to 1.5), who reported chemsex (HR = 1.3, 95% CI: 1.1 to 1.7), with a sexually transmitted infection history (HR = 1.5; 95% CI: 1.3 to 1.7), and who returned for their first nPEP follow-up visit (HR = 3.4, 95% CI: 2.7 to 4.2) had higher rates of PrEP linkage. There was no difference in PrEP persistence between nPEP-to-PrEP and PrEP only participants. CONCLUSION: Over one-third of nPEP users were subsequently prescribed PrEP. However, the large proportion of men who repeatedly use nPEP calls for more efficient PrEP-linkage services and, among those who use PrEP, improved persistence should be encouraged.

Polyfunctional Fc Dependent Activity of Antibodies to Native Trimeric Envelope in HIV Elite Controllers.

Antibody dependent (AD) functions such as AD cellular cytotoxicity (ADCC) were associated with lower viral load (VL) in untreated HIV progressors and protection from HIV infection in the modestly protective RV144 HIV vaccine trial. Target cells used to measure ADCC, AD complement deposition (ADCD), and AD cellular trogocytosis (ADCT) have been either HIV envelope (Env) gp120-coated CEM.NKr.CCR5 cells or HIV infected cell cultures. In HIV infected cell cultures, uninfected bystander cells take up gp120 shed from infected cells. Both gp120-coated and gp120+ bystander cells expose CD4 induced (CD4i) epitopes, which are normally hidden in native trimeric Env expressed by genuinely HIV infected cells since Nef and Vpu downmodulate cell surface CD4. Antibody dependent assays using either of these target cells probe for CD4i Abs that are abundant in HIV+ plasma but that do not recognize HIV-infected cells. Here, we examined ADCC, ADCD, and ADCT functions using a target cell line, sorted HIV-infected cell line cells, whose HIV infection frequency nears 100% and that expresses HIV Env in a native trimeric closed conformation. Using sorted HIV-infected cells (siCEM) as targets, we probed the binding and AD functions of anti-gp120/Env Abs in plasma from HIV-infected untreated progressor (UTP, n = 18) and treated (TP, n = 24) subjects, compared to that in Elite controllers (EC, n = 37) and Viral Controllers (VC, n = 16), which are rare subsets of HIV-infected individuals who maintain undetectable or low VL, respectively, without treatment. Gp120-coated beads were used to measure AD cellular phagocytosis. Equivalent concentrations of input IgG in plasma from UTPs, ECs, and VCs supported higher levels of all AD functions tested than plasma from TPs. When AD activities were normalized to the concentration of anti-gp120/Env-specific Abs, between-group differences largely disappeared. This finding suggests that the anti-gp120/Env Abs concentrations and not their potency determined AD functional levels in these assays. Elite controllers did differ from the other groups by having AD functions that were highly polyfunctional and highly correlated with each other. PCR measurement of HIV reservoir size showed that ADCC activity was higher in ECs and VCs with a reservoir size below the limit of detection compared to those having a measurable HIV reservoir size.

Vitamin E is an effective treatment for nonalcoholic steatohepatitis in HIV mono-infected patients.

OBJECTIVE: HIV-infected patients are at increased risk of nonalcoholic steatohepatitis (NASH). Vitamin E is recommended for treatment of NASH in the general population. However, its safety and efficacy among HIV-infected patients remain unknown. DESIGN: Single-centre, phase IV, open-label, single arm clinical trial. METHODS: HIV mono-infected patients without significant alcohol intake or viral hepatitis coinfection were included. The diagnosis of NASH was based on the co-existence of fatty liver, diagnosed by controlled attenuation parameter (CAP) at least 248 dB/m and significant hepatocyte apoptosis, defined by the serum biomarker cytokeratin 18 (CK-18) greater than 130.5 U/L. Participants were treated with 800 IU daily of oral vitamin E (alpha-tocopherol) for 24 weeks, and followed for an additional 24 weeks postdiscontinuation. Generalized linear mixed effects models were used to evaluate changes in alanine aminotransferase (ALT), CAP and CK-18 at the completion of treatment and end of follow-up, controlling for pretreatment trends. RESULTS: A total of 27 patients were included. Four (15%) had a pretreatment liver biopsy, which confirmed the diagnosis of NASH in all cases. Compared with baseline, 24 weeks of vitamin E treatment improved ALT [-27 units/l; 95% confidence interval (CI) -37 to -17], CAP scores (-22 dB/m; 95% CI -42 to -1) and CK-18 (-123 units/l; 95% CI -201 to -46). Conversely, there was no change in BMI. No serious adverse event was reported and no patient was lost to follow-up. CONCLUSION: In this first clinical trial, we showed that vitamin E is an effective and well tolerated treatment for NASH in HIV-infected patients.

Cannabis Consumption in People Living with HIV: Reasons for Use, Secondary Effects, and Opportunities for Health Education.

Introduction: Rates of cannabis consumption range from 40% to 74% among people living with HIV (PLWH). Little is known about the reasons for cannabis use, related modes of administration, effectiveness for symptom relief, or undesirable effects in the modern antiretroviral therapy (ART) era. Our aim was to conduct an exploratory study to identify potential areas for further evaluation and intervention. Materials and Methods: From January to June 2018, health care providers at the Chronic Viral Illness Service in Montreal, Canada, asked their patients about cannabis use during routine visits. Patients reporting cannabis use were invited to complete a 20-min coordinator-administered questionnaire. Questions related to patterns of use, modes of administration, reasons for use, secondary effects, and HIV health-related factors (e.g., adherence to ART). Results: One hundred and four PLWH reporting cannabis use participated. Median age was 54 years (interquartile range [IQR] 46-59), 13% were female, and 42% were HIV-Hepatitis C co-infected. Median CD4 count was 590 cells/mm3 (IQR 390-821), 95% of participants were on ART, and 88% had suppressed viral loads. Reported cannabis use was more than once daily (32%); daily (25%); weekly (22%); monthly (17%); and rarely (twice to thrice per year; 6%). The majority of participants (97%) smoked dry plant cannabis. Other modes included vaping (12%), capsules (2%), edibles (21%), and oils (12%). Common reasons for cannabis use were for pleasure (68%) and to reduce anxiety (57%), stress (55%), and pain (57%). Many participants found cannabis "quite effective" or "extremely effective" (45%) for symptom relief. Secondary effects included feeling high (74%), increased cough (45%), paranoia (22%), palpitations (20%), and increased anxiety (21%). Over two-thirds of participants indicated that secondary effects were not bothersome at all. Most participants (68%) rarely missed doses of their ART, while 27% missed occasionally (once to twice per month). The most commonly accessed sources of information about cannabis were friends (77%) and the internet (55%). Conclusion: The most common reasons for cannabis use in our population were for pleasure, followed by reduction of stress/anxiety and symptoms associated with a medical condition. Most smoke cannabis and rate cannabis as quite effective for symptom relief. While many participants experience secondary effects, most are not bothered by these symptoms. Amid widespread changes in the regulatory landscape of recreational cannabis, health care providers should be prepared to answer questions about cannabis.

Cohort profile: l'Actuel Pre-Exposure Prophylaxis (PrEP) Cohort study in Montreal, Canada.

PURPOSE: The l'Actuel PrEP Cohort was established to monitor the uptake, effectiveness, safety and changes in sexual risk behaviours among individuals receiving pre-exposure prophylaxis (PrEP) for the prevention of HIV. This prospective dynamic cohort is based at Clinique médicale l'Actuel, a large sexual health clinic located in Montreal, Canada. PARTICIPANTS: Since the cohort inception in January of 2013 through June 2018, 2156 individuals consulted for PrEP as participants in the l'Actuel PrEP Cohort. Median age was 35 years (IQR: 29-44 years) and the majority (96%) were men who have sex with men. Among 1551 individuals who initiated PrEP care, the median duration of follow-up was 9.2 months (IQR: 3.7-19.6), with substantial variation based on year of cohort entry. The l'Actuel PrEP Cohort contains both daily and intermittent 'on-demand' PrEP users and has the largest reported population of intermittent PrEP users (n=406) in North America. FINDINGS TO DATE: No incident HIV infections have occurred among individuals using PrEP over 1637 person-years of follow-up. However, retention in PrEP care is essential as three individuals who discontinued PrEP subsequently acquired HIV, translating to an HIV incidence of 3.9 cases per 100 person-years (95% CI: 1.3 to 12.1). Among a sample of participants with 1 year of follow-up before and after PrEP initiation (n=109), a moderate increase in sexually transmitted infections was observed following PrEP start. FUTURE PLANS: The l'Actuel PrEP Cohort continues to grow with new participants starting PrEP monthly and extended follow-up for existing users. The cohort data will be used for ongoing monitoring of PrEP and for population-level modelling of the impact of PrEP on HIV incidence in Montreal.

Quantifying Anti-HIV Envelope-Specific Antibodies in Plasma from HIV Infected Individuals.

Quantifying HIV Envelope (Env)-specific antibodies in HIV+ plasma is useful for interpreting antibody dependent cellular cytotoxicity assay results. HIV Env, the only viral protein expressed on the surface of infected cells, has a native trimeric closed conformation on cells infected with wild-type HIV. However, CD4+ uninfected bystander cells in HIV+ cell cultures bind gp120 shed from HIV+ cells exposing CD4-induced epitopes normally hidden in native Env. We used flow-cytometry based assays to quantify antibodies in HIV+ plasma specific for native trimeric Env or gp120/CD4 conjugates using CEM.NKr.CCR5 (CEM) cells infected with HIV (iCEM) or coated with recombinant gp120 (cCEM), as a surrogate for gp120+ HIV- bystander cells. Results from both assays were compared to those of a plate-based ELISA to monomeric gp120. The levels of Env-specific antibodies to cCEM and iCEM, measured by flow cytometry, and to gp120 by ELISA were positively correlated. More antibodies in HIV+ plasma recognized the gp120 conformation exposed on cCEM than on iCEM. Comparisons of plasma from untreated progressors, treated progressors, and elite controllers revealed that antibodies to Env epitopes were the lowest in treated progressors. Plasma from elite controllers and untreated progressors had similarly high levels of Env-specific antibodies, despite elite controllers having undetectable HIV viral loads, while untreated progressors maintained high viral loads.

CXCL13 as a Biomarker of Immune Activation During Early and Chronic HIV Infection.

Background: CXCL13 is preferentially secreted by Follicular Helper T cells (TFH) to attract B cells to germinal centers. Plasma levels of CXCL13 have been reported to be elevated during chronic HIV-infection, however there is limited data on such elevation during early phases of infection and on the effect of ART. Moreover, the contribution of CXCL13 to disease progression and systemic immune activation have been partially defined. Herein, we assessed the relationship between plasma levels of CXCL13 and systemic immune activation. Methods: Study samples were collected in 114 people living with HIV (PLWH) who were in early (EHI) or chronic (CHI) HIV infection and 35 elite controllers (EC) compared to 17 uninfected controls (UC). A subgroup of 11 EHI who initiated ART and 14 who did not were followed prospectively. Plasma levels of CXCL13 were correlated with CD4 T cell count, CD4/CD8 ratio, plasma viral load (VL), markers of microbial translocation [LPS, sCD14, and (1→3)-ß-D-Glucan], markers of B cell activation (total IgG, IgM, IgA, and IgG1-4), and inflammatory/activation markers like IL-6, IL-8, IL-1ß, TNF-α, IDO-1 activity, and frequency of CD38+HLA-DR+ T cells on CD4+ and CD8+ T cells. Results: Plasma levels of CXCL13 were elevated in EHI (127.9 ± 64.9 pg/mL) and CHI (229.4 ± 28.5 pg/mL) compared to EC (71.3 ± 20.11 pg/mL), and UC (33.4 ± 14.9 pg/mL). Longitudinal analysis demonstrated that CXCL13 remains significantly elevated after 14 months without ART (p < 0.001) and was reduced without normalization after 24 months on ART (p = 0.002). Correlations were observed with VL, CD4 T cell count, CD4/CD8 ratio, LPS, sCD14, (1→3)-ß-D-Glucan, total IgG, TNF-α, Kynurenine/Tryptophan ratio, and frequency of CD38+HLA-DR+ CD4 and CD8 T cells. In addition, CMV+ PLWH presented with higher levels of plasma CXCL13 than CMV- PLWH (p = 0.005). Conclusion: Plasma CXCL13 levels increased with HIV disease progression. Early initiation of ART reduces plasma CXCL13 and B cell activation without normalization. CXCL13 represents a novel marker of systemic immune activation during early and chronic HIV infection and may be used to predict the development of non-AIDS events.

Oral cannabinoids in people living with HIV on effective antiretroviral therapy: CTN PT028-study protocol for a pilot randomised trial to assess safety, tolerability and effect on immune activation.

INTRODUCTION: Despite antiretroviral therapy (ART), people living with HIV have higher rates of non-infectious chronic diseases. These conditions are driven by relatively high levels of inflammation persisting on ART compared with uninfected individuals. Chronic inflammation also contributes to HIV persistence during ART. Cannabis when taken orally may represent a way to reduce inflammation and strengthen immune responses. Before planning large interventional studies, it is important to ensure that cannabis taken orally is safe and well tolerated in people living with HIV. We propose to conduct a pilot randomised trial to examine the safety and tolerability of cannabis oils containing tetrahydrocannabinol (THC) and cannabidiol (CBD) consumed orally in people living with HIV. We will also measure inflammatory markers, markers of HIV persistence in peripheral blood cells and changes in the gastrointestinal microbiome. METHODS AND ANALYSIS: Twenty-six people living with HIV having undetectable viral load for at least 3 years will be randomised to receive TN-TC11LM (THC:CBD in 1:1 ratio) or TN-TC19LM (THC:CBD in 1:9 ratio) capsules daily for 12 weeks. Safety and tolerability of these capsules will be assessed through haematological, hepatic and renal blood tests, face-to-face interviews and questionnaires. Proportions of participants without any signs of significant toxicity (grades 0-2 scores on the WHO toxicity scale) and who complete the study, as well as scores on quality of life and mood will be examined using descriptive statistics. The effects on inflammatory markers, markers of peripheral blood reservoir size and effect on the composition of the gastrointestinal microbiome will be assessed before and after study completion. ETHICS AND DISSEMINATION: This study has been approved by the Research Institute of the McGill University Health Centre. A Data Safety Monitor will review safety information at regular intervals. The final manuscript will be submitted to an open-access journal within 6 months of study completion. TRIAL REGISTRATION NUMBER: NCT03550352.

Angiocentric lymph proliferative disorder (lymphomatoid granulomatosis) in a person with newly-diagnosed HIV infection: a case report.

BACKGROUND: Angiocentric lymph proliferative disorder (ALPD) is a granulomatous lymphoproliferative condition associated with various primary and secondary immunodeficiency states. ALPD is so rare that its prevalence has not been established. Typically affecting middle-aged adults, this condition is often found in the context of Epstein Bar Virus infection and consists of angiocentric and angioinvasive pulmonary infiltrates. Herein, we present a biopsy-proven case of a patient manifesting with a viral meningoencephalomyelitis-like picture with brain, spinal cord, renal and splenic lesions. The diagnosis was confirmed to be ALPD in the context of newly diagnosed HIV infection. CASE PRESENTATION: A 35 year-old homosexual man presented with a 5-week history of headaches followed by a 3-week history of horizontal diplopia, limb weakness and right 6th cranial nerve palsy. Lumbar puncture revealed a lymphocytic pleocytosis, high protein and low glucose. Magnetic Resonance Imaging showed scattered lesions throughout the brain and spinal cord and Computed Tomography of the abdomen and pelvis revealed hypodensities involving the kidneys and spleen. HIV testing was positive, with a viral load of 11,096 copies/mL and CD4 count of 324 cells/µL. Serum Epstein Bar virus PCR was positive with 12,434 copies/ml. Right frontal brain biopsy revealed gray matter containing angiogentric cerebritis with organizing infarction but Epstein Bar Virus-in situ preparations were negative and no viral inclusions were identified. A diagnosis of ALPD (also known as lymphomatoid granulomatosis) was made. The patient was initiated on antiretroviral therapy and treated with intravenous rituximab every 3 weeks for 4 cycles and made progressive improvements. By the time of discharge his strength had improved and he was ambulating again although with a walker. Within 2 months, his HIV viral load was suppressed. Magnetic Resonance Imaging of the brain 6 months later revealed interval improvement. At his most recent follow-up, 34 months later, his neurological symptoms had almost completed resolved. CONCLUSION: Albeit rare, ALPD should be considered in the differential diagnosis of central nervous system lesions in persons with HIV once common etiologies have been eliminated. Furthermore, ALPD involving the central nervous system may occur in in the absence of documented EBV infection in the central nervous system.

Nasal Nitric Oxide Levels in HIV Infection: A Cross-Sectional Study.

INTRODUCTION: Low levels of nasal NO have been associated with increased propensity to rhinosinusitis and respiratory tract infections. Our objective was to describe nasal NO levels in HIV-infected individuals versus healthy controls and determine possible risk factors for reduced nasal NO levels. MATERIALS AND METHODS: HIV-infected individuals and healthy controls were recruited. Participants underwent nasal NO testing by standardized methods using a CLD88 chemiluminescence analyzer and completed the Sinonasal Outcome Test-20 (SNOT-20) on symptoms of rhinosinusitis. RESULTS: Participants included 41 HIV-infected individuals with suppressed VL on antiretroviral therapy (ART group), 5 HIV-infected individuals with detectable VL off ART (viremic group), and 12 healthy controls (HC group). Mean nasal NO level was 253 (±77) nL/min in the ART group, 213 (±48) nL/min in the viremic group, and 289 (±68) nL/min in the HC group (p = 0.133; ANOVA). There was no correlation between nasal NO level and VL in viremic individuals (r = -0.200; p = 0.747). Differences were observed in mean total points on the SNOT-20 which were 19 (±16)/100, 18 (±26)/100, and 4 (±4)/100 in the ART, viremic, and HC groups, respectively (p = 0.013; ANOVA). CONCLUSION: Healthy individuals, HIV patients on ART, and viremic individuals off ART display similar nasal NO levels. However, rhinosinusitis symptoms remain prominent despite ART-treatment.

Socio-economic status and time trends associated with early ART initiation following primary HIV infection in Montreal, Canada: 1996 to 2015.

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 <180 days. The median interquartile range (IQR) age of participants was 35 (28; 42) years and the majority were male (96%), having paid employment (63%), men who have sex with men (MSM) (78%) and one to four sexual partners in the last three months (70%). Participants presented with a median IQR HIV plasma viral load of 4.6 (3.7; 5.3) log10 copies/ml, CD4 count of 510 (387; 660) cells/µl and were recruited in CMCs (52%) or UMCs (48%). Early ART initiation was observed in 47% of the participants and the trend followed a V-shaped curve with peaks in 1996 to 1997 (89%) and 2013 to 2015 (88%) with a dip in 2007 to 2009 (22%). Multivariable analyses showed that having a paid employment adjusted odds ratio (aOR: 2.43; 95% CI: 1.19, 4.95), lower CD4 count (aOR per 50 cell increase: 0.93; 95% CI: 0.87, 0.99) and care at UMCs (aOR: 2.03; 95% CI: 1.06 to 3.90) were independently associated with early ART initiation. 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.

Screening for nonalcoholic steatohepatitis by using cytokeratin 18 and transient elastography in HIV mono-infection.

BACKGROUND AND AIM: HIV-infected individuals are at high risk of developing nonalcoholic steatohepatitis (NASH), a leading cause of end-stage liver disease in Western countries. Nonetheless, due to the invasiveness of liver biopsy, NASH remains poorly understood in HIV mono-infection. We aimed to characterize the prevalence and predictors of NASH in unselected HIV mono-infected patients by means of non-invasive diagnostic tools. METHODS: HIV-infected adults without significant alcohol intake or co-infection with hepatitis B or C underwent a routine screening program employing transient elastography (TE) with controlled attenuation parameter (CAP) and the serum biomarker cytokeratin-18 (CK-18). NASH was diagnosed non-invasively as the coexistence of fatty liver (CAP ≥248 dB/m) and CK-18 >246 U/L. Identified cases of NASH were offered a diagnostic liver biopsy. Predictors of NASH were determined by multivariate logistic regression analysis. RESULTS: 202 consecutive HIV mono-infected patients were included. NASH was non-invasively diagnosed in 23 cases (11.4%). Among them, 17 underwent a liver biopsy, and histology confirmed NASH in all cases. The prevalence of NASH was higher in patients with hypertriglyceridemia (17.1%), insulin resistance defined by homeostasis model for assessment of insulin resistance (HOMA-IR) (25%), those with detectable HIV viral load (42.9%) and those with elevated ALT (53.6%). After adjustment, higher HOMA-IR (adjusted odds ratio [aOR] = 1.20, 95% CI 1.01-1.43; p = 0.03) and ALT (aOR = 2.39, 95% CI 1.50-3.79; p<0.001) were independent predictors of NASH. CONCLUSIONS: NASH, diagnosed by a non-invasive diagnostic approach employing CK-18 and TE with CAP, is common in unselected HIV mono-infected individuals, particularly in the presence of insulin resistance and elevated ALT.