Associations of CD4 Cell Count Measures With Infection-Related and Infection-Unrelated Cancer Risk Among People With HIV.

BACKGROUND: People with HIV are at higher risk of infection-related cancers than the general population, which could be due, in part, to immune dysfunction. Our objective was to examine associations between 4 CD4 count measures as indicators of immune function and infection-related and infection-unrelated cancer risk. SETTING: We conducted a cohort study of adults with HIV who were diagnosed with cancer in Ontario, Canada. Incident cancers were identified from January 1, 1997 to December 31, 2020. METHODS: We estimated adjusted hazard ratios (aHR) for the associations between CD4 measures (baseline CD4, nadir CD4, time-updated CD4, time-updated CD4:CD8) and cancer incidence rates using competing risk analyses, adjusted for socio-demographic factors, history of hepatitis B or C infection, baseline viral load, smoking, and alcohol use. RESULTS: Among 4771 people with HIV, contributing 59,111 person-years of observation, a total of 549 cancers were observed. Low baseline CD4 (<200 cells/µL) (aHR 2.08 [95% CI: 1.38 to 3.13], nadir (<200 cells/µL) (aHR 2.01 [95% CI: 1.49 to 2.71]), low time-updated CD4 (aHR 3.52 [95% CI: 2.36 to 5.24]) and time-updated CD4:CD8 ratio (<0.4) (aHR 2.02 [95% CI: 1.08 to 3.79]) were associated with an increased rate of infection-related cancer. No associations were observed for infection-unrelated cancers. CONCLUSIONS: Low CD4 counts and indices were associated with increased rates of infection-related cancers among people with HIV, irrespective of the CD4 measure used. Early diagnosis and linkage to care and high antiretroviral therapy uptake may lead to improved immune function and could add to cancer prevention strategies such as screening and vaccine uptake.

Trends in infection-related and infection-unrelated cancer incidence among people with and without HIV infection in Ontario, Canada, 1996-2020: a population-based matched cohort study using health administrative data.

BACKGROUND: People with HIV infection are at higher risk for certain cancers than the general population. We compared trends in infection-related and infection-unrelated cancers among people with and without HIV infection. METHODS: We conducted a retrospective population-based matched cohort study of adults with and without HIV infection using linked health administrative databases in Ontario, Canada. Participants were matched on birth year, sex, census division (rurality), neighbourhood income quintile and region of birth. We followed participants from cohort entry until the earliest of date of cancer diagnosis, date of death, Nov. 1, 2020, or date of loss to follow-up. Incident cancers identified from Jan. 1, 1996, to Nov. 1, 2020, were categorized as infection-related or-unrelated. We examined calendar periods 1996-2003, 2004-2011 and 2012-2020, corresponding to the early combination antiretroviral therapy (cART), established cART and contemporary cART eras, respectively. We used competing risk analyses to examine trends in cumulative incidence by calendar period, age and sex, and cause-specific hazard ratios (HRs). RESULTS: We matched 20 304 people with HIV infection to 20 304 people without HIV infection. A total of 2437 cancers were diagnosed, 1534 (62.9%) among infected people and 903 (37.0%) among uninfected people. The risk of infection-related cancer by age 65 years for people with HIV infection decreased from 19.0% (95% confidence interval [CI] 15.6%-22.3%) in 1996-2011 to 10.0% (95% CI 7.9%-12.1%) in 2012-2020. Compared to uninfected people, those with HIV infection had similar HRs of infection-unrelated cancer but increased rates of infection-related cancer, particularly among younger age groups (25.1 [95% CI 13.2-47.4] v. 1.9 [95% CI 1.0-3.7] for age 18-39 yr v. ≥ 70 yr); these trends were consistent when examined by sex.Interpretation: We observed significantly higher rates of infection-related, but not infection-unrelated, cancer among people with HIV infection than among uninfected people. The elevated rate of infection-related cancer in 2012-2020 highlights the importance of early and sustained antiretroviral therapy along with cancer screening and prevention measures.

Coronavirus disease 2019 vaccine effectiveness among a population-based cohort of people living with HIV.

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.

The burden of cancer among people living with HIV in Ontario, Canada, 1997-2020: a retrospective population-based cohort study using administrative health data.

BACKGROUND: With combination antiretroviral therapy (ART) and increased longevity, cancer is a leading cause of morbidity among people with HIV. We characterized trends in cancer burden among people with HIV in Ontario, Canada, between 1997 and 2020. METHODS: We conducted a population-based, retrospective cohort study of adults with HIV using linked administrative health databases from Jan. 1, 1997, to Nov. 1, 2020. We grouped cancers as infection-related AIDS-defining cancers (ADCs), infection-related non-ADCs (NADCs) and infection-unrelated cancers. We calculated age-standardized incidence rates per 100 000 person-years with 95% confidence intervals (CIs) using direct standardization, stratified by calendar period and sex. We also calculated limited-duration prevalence. RESULTS: Among 19 403 adults living with HIV (79% males), 1275 incident cancers were diagnosed. From 1997-2000 to 2016- 2020, we saw a decrease in the incidence of all cancers (1113.9 [95% CI 657.7-1765.6] to 683.5 [95% CI 613.4-759.4] per 100 000 person-years), ADCs (403.1 [95% CI 194.2-739.0] to 103.8 [95% CI 79.2-133.6] per 100 000 person-years) and infection-related NADCs (196.6 [95% CI 37.9-591.9] to 121.9 [95% CI 94.3-154.9] per 100 000 person-years). The incidence of infection-unrelated cancers was stable at 451.0 per 100 000 person-years (95% CI 410.3-494.7). The incidence of cancer among females increased over time but was similar to that of males in 2016-2020. INTERPRETATION: Over a 24-year period, the incidence of cancer decreased overall, largely driven by a considerable decrease in the incidence of ADC, whereas the incidence of infection-unrelated cancer remained unchanged and contributed to the greatest burden of cancer. These findings could reflect combination ART-mediated changes in infectious comorbidity and increased life expectancy; targeted cancer screening and prevention strategies are needed.

Measures of HIV Pre-exposure Prophylaxis Uptake Among Gay, Bisexual, and Other Men Who Have Sex with Men in Canada and Demographic Disparities Among Those at Elevated Likelihood for HIV Acquisition.

HIV pre-exposure prophylaxis (PrEP) is an effective prevention tool being scaled up in Canada. We describe PrEP uptake and identify demographic correlates of uptake among gay, bisexual, and other men who have sex with men (gbMSM) at elevated HIV risk using data from an online survey of gbMSM residing in Canada between Oct 2017 and Jan 2018. Among the 969 participants at elevated HIV risk who had recently tested for HIV, 96.0%, 83.3%, 72.6%, and 39.7% reported awareness, knowledge, acceptability, and pursuit of PrEP, respectively; 27.1% had ever and 24.6% were currently taking PrEP. The strongest correlate of PrEP uptake was living in a city of ≥ 500,000 inhabitants; others included being out to all or almost all family, friends, and colleagues regarding sexual attraction to men, greater financial coping, and being 30-49 years of age. Improved upscaling of PrEP in Canada may be accomplished through consideration of these disparities.

Cohort profile: Development and profile of a population-based, retrospective cohort of diagnosed people living with HIV in Ontario, Canada (Ontario HIV Laboratory Cohort).

PURPOSE: Population-based cohorts of diagnosed people living with HIV (PLWH) are limited worldwide. In Ontario, linked HIV diagnostic and viral load (VL) test databases are centralised and contain laboratory data commonly used to measure engagement in HIV care. We used these linked databases to create a population-based, retrospective cohort of diagnosed PLWH in Ontario, Canada. PARTICIPANTS: A datamart was created by integrating diagnostic and VL databases and linking records at the individual level. These databases contain information on laboratory test results and sociodemographic/clinical information collected on requisition/surveillance forms. Datamart individuals enter our cohort with the first record of a nominal HIV-positive diagnostic test (1985-2015) or VL test (1996-2015), and remain unless administratively lost to follow-up (LTFU; no VL test for >2 years and no VL test in later years). Non-nominal diagnostic tests are excluded as they lack identifying information to permit linkage to other tests. However, individuals diagnosed non-nominally are included in the cohort with record of a VL test. The LTFU rule is applied to indirectly censor for death/out-migration. FINDINGS TO DATE: As of the end of 2015, the datamart contained 40 372 HIV-positive diagnostic tests and 23 851 individuals with ≥1 VL test. Almost half (46.3%) of the diagnostic tests were non-nominal and excluded, although this was lower (~15%) in recent years. Overall, 29 587 individuals have entered the cohort-contributing 229 302 person-years of follow-up since 1996. Between 2000 and 2015, the number of diagnosed PLWH (cohort individuals not LTFU) increased from 8859 to 16 110, and the percent who were aged ≥45 years increased from 29.1% to 62.6%. The percent of diagnosed PLWH who were virally suppressed (<200 copies/mL) increased from 40.7% in 2000 to 79.5% in 2015. FUTURE PLANS: We plan to conduct further analyses of HIV care engagement and link to administrative databases with information on death, migration, physician billing claims and prescriptions. Linkage to other data sources will address cohort limitations and expand research opportunities.

Trends in HIV care cascade engagement among diagnosed people living with HIV in Ontario, Canada: A retrospective, population-based cohort study.

BACKGROUND: The HIV cascade is an important framework for assessing systems of care, but population-based assessment is lacking for most jurisdictions worldwide. We measured cascade indicators over time in a population-based cohort of diagnosed people living with HIV (PLWH) in Ontario, Canada. METHODS: We created a retrospective cohort of diagnosed PLWH using a centralized laboratory database with HIV diagnostic and viral load (VL) test records linked at the individual-level. Individuals enter the cohort with record of a nominal HIV-positive diagnostic test or VL test, and remain unless administratively lost to follow-up (LTFU, >2 consecutive years with no VL test and no VL test in later years). We calculated the annual percent of diagnosed PLWH (cohort individuals not LTFU) between 2000 and 2015 who were in care (≥1 VL test), on ART (as documented on VL test requisition) or virally suppressed (<200 copies/ml). We also calculated time from diagnosis to linkage to care and viral suppression among individuals newly diagnosed with HIV. Analyses were stratified by sex and age. Upper/lower bounds were calculated using alternative indicator definitions. RESULTS: The number of diagnosed PLWH increased from 8,859 (8,859-11,389) in 2000 to 16,110 (16,110-17,423) in 2015. Over this 16-year period, the percent of diagnosed PLWH who were: in care increased from 81% (63-81%) to 87% (81-87%), on ART increased from 55% (34-60%) to 81% (70-82%) and virally suppressed increased from 41% (23-46%) to 80% (67-81%). Between 2000 and 2014, the percent of newly diagnosed individuals who linked to care within three months of diagnosis or achieved viral suppression within six months of diagnosis increased from 67% to 82% and from 22% to 42%, respectively. Estimates were generally lower for females and younger individuals. DISCUSSION: HIV cascade indicators among diagnosed PLWH in Ontario improved between 2000 and 2015, but gaps still remain-particularly for younger individuals.

Alternate interfaces may mediate homomeric and heteromeric assembly in the transmembrane domains of SNARE proteins.

The fusion of a vesicle to a target membrane is mediated by temporally and spatially regulated interactions within a set of evolutionarily conserved proteins. Integral to proper fusion is the interaction between proteins originating on both vesicle and target membranes to form a protein bridge between the two membranes, known as the SNARE complex. This protein complex includes the single-pass transmembrane helix proteins: syntaxin and synaptobrevin. Experimental data and amino acid sequence analysis suggest that an interface of interaction is conserved between the transmembrane regions of the two proteins. However, conflicting reports have been presented on the role of the synaptobrevin transmembrane domain in mediating important protein-protein interactions. To address this question, a thermodynamic study was carried out to determine quantitatively the self-association propensities of the transmembrane domains of synaptobrevin and syntaxin. Our results show that the transmembrane domain of synaptobrevin has only a modest ability to self-associate, whereas the transmembrane domain of syntaxin is able to form stable homodimers. Nevertheless, by a single amino acid substitution, synaptobrevin can be driven to dimerize with the same affinity as syntaxin. Furthermore, crosslinking studies show that dimerization of synaptobrevin is promoted by oxidizing agents. Despite the presence of a conserved cysteine residue in the same location as in synaptobrevin, syntaxin dimerization is not promoted by oxidization. This analysis suggests that subtle yet distinct differences are present between the two transmembrane dimer interfaces. A syntaxin/synaptobrevin heterodimer is able to form under oxidizing conditions, and we propose that the interface of interaction for the heterodimer may resemble the homodimer interface formed by the synaptobrevin transmembrane domain. Computational analysis of the transmembrane sequences of syntaxin and synaptobrevin reveal structural models that correlate with the experimental data. These data may provide insight into the role of transmembrane segments in the mechanism of vesicle fusion.