Exploring the dynamics of the 2022 mpox outbreak in Canada.

The 2022 mpox outbreak predominantly impacted gay, bisexual, and other men who have sex with men (gbMSM). Two models were developed to support situational awareness and management decisions in Canada. A compartmental model characterized epidemic drivers at national/provincial levels, while an agent-based model (ABM) assessed municipal-level impacts of vaccination. The models were parameterized and calibrated using empirical case and vaccination data between 2022 and 2023. The compartmental model explored: (1) the epidemic trajectory through community transmission, (2) the potential for transmission among non-gbMSM, and (3) impacts of vaccination and the proportion of gbMSM contributing to disease transmission. The ABM incorporated sexual-contact data and modeled: (1) effects of vaccine uptake on disease dynamics, and (2) impacts of case importation on outbreak resurgence. The calibrated, compartmental model followed the trajectory of the epidemic, which peaked in July 2022, and died out in December 2022. Most cases occurred among gbMSM, and epidemic trajectories were not consistent with sustained transmission among non-gbMSM. The ABM suggested that unprioritized vaccination strategies could increase the outbreak size by 47%, and that consistent importation (≥5 cases per 10 000) is necessary for outbreak resurgence. These models can inform time-sensitive situational awareness and policy decisions for similar future outbreaks.

Population-level effectiveness of pre-exposure prophylaxis for HIV prevention among men who have sex with men in Montréal (Canada): a modelling study of surveillance and survey data.

INTRODUCTION: HIV pre-exposure prophylaxis (PrEP) has been recommended and partly subsidized in Québec, Canada, since 2013. We evaluated the population-level impact of PrEP on HIV transmission among men who have sex with men (MSM) in Montréal, Québec's largest city, over 2013-2021. METHODS: We used an agent-based mathematical model of sexual HIV transmission to estimate the fraction of HIV acquisitions averted by PrEP compared to a counterfactual scenario without PrEP. The model was calibrated to local MSM survey, surveillance, and cohort data and accounted for COVID-19 pandemic impacts on sexual activity, HIV prevention, and care. PrEP was modelled from 2013 onwards, assuming 86% individual-level effectiveness. The PrEP eligibility criteria were: any anal sex unprotected by condoms (past 6 months) and either multiple partnerships (past 6 months) or multiple uses of post-exposure prophylaxis (lifetime). To assess potential optimization strategies, we modelled hypothetical scenarios prioritizing PrEP to MSM with high sexual activity (≥11 anal sex partners annually) or aged ⩽45 years, increasing coverage to levels achieved in Vancouver, Canada (where PrEP is free-of-charge), and improving retention. RESULTS: Over 2013-2021, the estimated annual HIV incidence decreased from 0.4 (90% credible interval [CrI]: 0.3-0.6) to 0.2 (90% CrI: 0.1-0.2) per 100 person-years. PrEP coverage among HIV-negative MSM remained low until 2015 (<1%). Afterwards, coverage increased to a maximum of 10% of all HIV-negative MSM, or about 16% of the 62% PrEP-eligible HIV-negative MSM in 2020. Over 2015-2021, PrEP averted an estimated 20% (90% CrI: 11%-30%) of cumulative HIV acquisitions. The hypothetical scenarios modelled showed that, at the same coverage level, prioritizing PrEP to high sexual activity MSM could have averted 30% (90% CrI: 19%-42%) of HIV acquisitions from 2015-2021. Even larger impacts could have resulted from higher coverage. Under the provincial eligibility criteria, reaching 10% coverage among HIV-negative MSM in 2015 and 30% in 2019, like attained in Vancouver, could have averted up to 63% (90% CrI: 54%-70%) of HIV acquisitions from 2015 to 2021. CONCLUSIONS: PrEP reduced population-level HIV transmission among Montréal MSM. However, our study suggests missed prevention opportunities and adds support for public policies that reduce PrEP barriers, financial or otherwise, to MSM at risk of HIV acquisition.

Population-level impact of expanding PrEP coverage by offering long-acting injectable PrEP to MSM in three high-resource settings: a model comparison analysis.

INTRODUCTION: Long-acting injectable cabotegravir (CAB-LA) demonstrated superiority to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis (PrEP) in the HPTN 083/084 trials. We compared the potential impact of expanding PrEP coverage by offering CAB-LA to men who have sex with men (MSM) in Atlanta (US), Montreal (Canada) and the Netherlands, settings with different HIV epidemics. METHODS: Three risk-stratified HIV transmission models were independently parameterized and calibrated to local data. In Atlanta, Montreal and the Netherlands, the models, respectively, estimated mean TDF/FTC coverage starting at 29%, 7% and 4% in 2022, and projected HIV incidence per 100 person-years (PY), respectively, decreasing from 2.06 to 1.62, 0.08 to 0.03 and 0.07 to 0.001 by 2042. Expansion of PrEP coverage was simulated by recruiting new CAB-LA users and by switching different proportions of TDF/FTC users to CAB-LA. Population effectiveness and efficiency of PrEP expansions were evaluated over 20 years in comparison to baseline scenarios with TDF/FTC only. RESULTS: Increasing PrEP coverage by 11 percentage points (pp) from 29% to 40% by 2032 was expected to avert a median 36% of new HIV acquisitions in Atlanta. Substantially larger increases (by 33 or 26 pp) in PrEP coverage (to 40% or 30%) were needed to achieve comparable reductions in Montreal and the Netherlands, respectively. A median 17 additional PYs on PrEP were needed to prevent one acquisition in Atlanta with 40% PrEP coverage, compared to 1000+ in Montreal and 4000+ in the Netherlands. Reaching 50% PrEP coverage by 2032 by recruiting CAB-LA users among PrEP-eligible MSM could avert >45% of new HIV acquisitions in all settings. Achieving targeted coverage 5 years earlier increased the impact by 5-10 pp. In the Atlanta model, PrEP expansions achieving 40% and 50% coverage reduced differences in PrEP access between PrEP-indicated White and Black MSM from 23 to 9 pp and 4 pp, respectively. CONCLUSIONS: Achieving high PrEP coverage by offering CAB-LA can impact the HIV epidemic substantially if rolled out without delays. These PrEP expansions may be efficient in settings with high HIV incidence (like Atlanta) but not in settings with low HIV incidence (like Montreal and the Netherlands).

Measuring progress towards reaching zero new HIV acquisitions among key populations in Québec (Canada) using routine surveillance data: a mathematical modelling study.

INTRODUCTION: Men who have sex with men (MSM) and people who inject drugs (PWID) are disproportionately impacted by the HIV epidemic in Canada. Having the second-highest provincial diagnosis rate, an improved understanding of the epidemic among these populations in Québec could aid ongoing elimination efforts. We estimated HIV incidence and other epidemic indicators among MSM and PWID in Montréal and across Québec using a back-calculation model synthesizing surveillance data. METHODS: We developed a deterministic, compartmental mathematical model stratified by age, HIV status and disease progression, and clinical care stages. Using AIDS and HIV diagnoses data, including self-reported time since the last negative test and laboratory results of CD4 cell count at diagnosis, we estimated HIV incidence in each population over 1975-2020 by modelling a cubic M-spline. The prevalence, undiagnosed fraction, fraction diagnosed that started antiretroviral treatment (ART) and median time to diagnosis were also estimated. Since the COVID-19 pandemic disrupted testing, we excluded 2020 data and explored this in sensitivity analyses. RESULTS: HIV incidence in all populations peaked early in the epidemic. In 2020, an estimated 97 (95% CrI: 33-227) and 266 (95% CrI: 103-508) HIV acquisitions occurred among MSM in Montréal and Québec, respectively. Among PWID, we estimated 2 (95% CrI: 0-14) and 6 (95% CrI: 1-26) HIV acquisitions in those same regions. With 2020 data, unless testing rates were reduced by 50%, these estimates decreased, except among Québec PWID, whose increased. Among all, the median time to diagnosis shortened to <2 years before 2020 and the undiagnosed fraction decreased to <10%. This fraction was higher in younger MSM, with 22% of 15-24 year-olds living with HIV in Montréal (95% CrI: 9-39%) and 31% in Québec (95% CrI: 17-48%) undiagnosed by 2020 year-end. Finally, ART access neared 100% in all diagnosed populations. CONCLUSIONS: HIV incidence has drastically decreased in MSM and PWID across Québec, alongside significant improvements in diagnosis and treatment coverage-and the 2013 introduction of pre-exposure prophylaxis. Despite this, HIV transmission continued. Effective efforts to halt this transmission and rapidly diagnose people who acquired HIV, especially among younger MSM, are needed to achieve elimination. Further, as the impacts of the COVID-19 pandemic on HIV transmission are understood, increased efforts may be needed to overcome these.

Past dynamics of HIV transmission among men who have sex with men in Montréal, Canada: a mathematical modeling study.

BACKGROUND: Gay, bisexual, and other men who have sex with men (gbMSM) experience disproportionate risks of HIV acquisition and transmission. In 2017, Montréal became the first Canadian Fast-Track City, setting the 2030 goal of zero new HIV infections. To inform local elimination efforts, we estimate the evolving role of prevention and sexual behaviours on HIV transmission dynamics among gbMSM in Montréal between 1975 and 2019. METHODS: Data from local bio-behavioural surveys were analyzed to develop, parameterize, and calibrate an agent-based model of sexual HIV transmission. Partnership dynamics, HIV's natural history, and treatment and prevention strategies were considered. The model simulations were analyzed to estimate the fraction of HIV acquisitions and transmissions attributable to specific groups, with a focus on age, sexual partnering level, and gaps in the HIV care-continuum. RESULTS: The model-estimated HIV incidence peaked in 1985 (2.3 per 100 person years (PY); 90% CrI: 1.4-2.9 per 100 PY) and decreased to 0.1 per 100 PY (90% CrI: 0.04-0.3 per 100 PY) in 2019. Between 2000-2017, the majority of HIV acquisitions and transmissions occurred among men aged 25-44 years, and men aged 35-44 thereafter. The unmet prevention needs of men with > 10 annual anal sex partners contributed 90-93% of transmissions and 67-73% of acquisitions annually. The primary stage of HIV played an increasing role over time, contributing to 11-22% of annual transmissions over 2000-2019. In 2019, approximately 70% of transmission events occurred from men who had discontinued, or never initiated antiretroviral therapy. CONCLUSIONS: The evolving HIV landscape has contributed to the declining HIV incidence among gbMSM in Montréal. The shifting dynamics identified in this study highlight the need for continued population-level surveillance to identify gaps in the HIV care continuum and core groups on which to prioritize elimination efforts.

Combination HIV Prevention Strategies Among Montreal Gay, Bisexual, and Other Men Who Have Sex with Men in the PrEP Era: A Latent Class Analysis.

Pre-exposure prophylaxis (PrEP) became publicly available in Quebec for gay, bisexual and other men who have sex with men (GBM) in 2013. We used baseline data from Engage, a cohort of GBM recruited by respondent-driven sampling, to examine patterns of combination HIV prevention use among Montreal GBM since PrEP became available. Latent class analysis, stratified by HIV status, was used to categorize GBM by self-reported use of biomedical and behavioural prevention strategies. Correlates of resulting classes were identified using multinomial logistic regression. Among HIV-negative/unknown GBM (n = 968), we identified four classes: low use of prevention (32%), condoms (40%), seroadaptive behaviour (21%), and biomedical (including PrEP; 7%). Those using prevention (condoms, seroadaptive behaviour, and biomedical) had a higher number of anal sex partners and were more likely to report a recent sexually transmitted infection diagnosis. GBM using biomedical prevention also had a higher level of formal education. Among GBM living with HIV (n = 200), we identified three classes: mainly antiretroviral treatment (ART) with viral suppression (53%), ART with viral suppression and condoms (19%), and ART with viral suppression and seroadaptive behaviour (18%). Again, the number of anal sex partners was higher among those using condoms and seroadaptive behaviours. Our findings show antiretroviral-based prevention, either alone or in combination with other strategies, is clearly a component of the HIV prevention landscape for GBM in Montreal. Nevertheless, PrEP uptake remains low, and there is a need to promote its availability more widely.

Data variability across Canadian administrative health databases: Differences in content, coding, and completeness.

PURPOSE: The Canadian Network for Observational Drug Effect Studies (CNODES) is a network of Canadian research centres using administrative data to conduct distributed drug safety and effectiveness studies. In this study, we compare the provincial administrative databases and illustrate the potential impact of database differences on a CNODES study about domperidone and the risk of ventricular tachyarrhythmia and sudden cardiac death (VT/SCD). METHODS: We assessed the impact of varying versions and precision of the International Classification of Diseases coding system in physician claims data, and the content and completeness of hospital discharge abstracts across CNODES sites, as these variations can introduce differences in the study cohorts formed and affect study results. RESULTS: In our study of 214 962 patients, hospital diagnosis type (such as most responsible, admitting, or secondary diagnosis) was missing in some provinces, resulting in misclassification of the outcome and variation in rates and risk estimates. Incidence rates of VT/SCD ranged from 19.8 (95% confidence interval [CI] 17.7-22.2) per 10 000 person-years in British Columbia to 53.4 (95% CI 50.3-56.5) in Quebec. While most provinces reported an increased risk of VT/SCD, a null effect was observed in Quebec (rate ratio 1.06; 95% CI 0.79-1.41). CONCLUSIONS: Distributed analyses allow for rapid responses to drug safety signals. However, variation in characteristics of the administrative data across research centres can influence study results. By identifying the sources of database heterogeneity, one can evaluate the potential biases these differences may introduce, highlighting the importance of considering such variation in distributed networks.

Extreme restriction design as a method for reducing confounding by indication in pharmacoepidemiologic research.

PURPOSE: Confounding by indication is a concern in observational pharmacoepidemiologic studies, including those that use active comparator, new user (ACNU) designs. Here, we present a method of restriction to an indication, which we call "extreme restriction," to reduce confounding in such studies. METHODS: As a case study, we evaluated the effect of proton pump inhibitors (PPIs) on hospitalization for community-acquired pneumonia (HCAP). PPI use has been associated with increased HCAP risk, but this association likely results from confounding by indication due to gastroesophageal reflux disease (GERD). Using the UK's Clinical Practice Research Datalink, we compared the risk of HCAP within 180 days between PPI users and histamine-2 receptor antagonist (H2RA) users in an ACNU cohort using Cox proportional hazard models with a time-fixed exposure definition adjusted for high-dimensional propensity score deciles. We then performed the same analysis on an "extremely-restricted" cohort of incident nonsteroidal anti-inflammatory drug (NSAID) users, some of whom received PPIs for prophylaxis. Because PPIs were given as prophylaxis in this population, confounding due to GERD should be limited. We compared effect estimates between ACNU and restricted cohorts to evaluate confounding in both analyses. RESULTS: In the ACNU cohort, PPIs were associated with an increased risk of HCAP (hazard ratio [HR]: 1.25; 95% confidence interval [CI]: 1.05, 1.47), but this association was not present in the restricted cohort (HR: 1.06; 95% CI: 0.75, 1.49). CONCLUSIONS: Restriction to a single indication for treatment may reduce confounding by indication in studies conducted in distributed data networks and other large databases.

National HIV testing and diagnosis coverage in sub-Saharan Africa: a new modeling tool for estimating the 'first 90' from program and survey data

HIV testing services (HTS) are a crucial component of national HIV responses. Learning one's HIV diagnosis is the entry point to accessing life-saving antiretroviral treatment and care. Recognizing the critical role of HTS, the Joint United Nations Programme on HIV/AIDS (UNAIDS) launched the 90-90-90 targets stipulating that by 2020, 90% of people living with HIV know their status, 90% of those who know their status receive antiretroviral therapy, and 90% of those on treatment have a suppressed viral load. Countries will need to regularly monitor progress on these three indicators. Estimating the proportion of people living with HIV who know their status (i.e. the 'first 90'), however, is difficult. Methods: We developed a mathematical model (henceforth referred to as 'Shiny90') that formally synthesizes population-based survey and HTS program data to estimate HIV status awareness over time. The proposed model uses country-specific HIV epidemic parameters from the standard UNAIDS Spectrum model to produce outputs that are consistent with other national HIV estimates. Shiny90 provides estimates of HIV testing history, diagnosis rates, and knowledge of HIV status by age and sex. We validate Shiny90 using both in-sample comparisons and out-of-sample predictions using data from three countries: Côte d'Ivoire, Malawi, and Mozambique. Results: In-sample comparisons suggest that Shiny90 can accurately reproduce longitudinal sex-specific trends in HIV testing. Out-of-sample predictions of the fraction of people living with HIV ever tested over a 4-to-6-year time horizon are also in good agreement with empirical survey estimates. Importantly, out-of-sample predictions of HIV knowledge of status are consistent (i.e. within 4% points) with those of the fully calibrated model in the three countries when HTS program data are included. The model's predictions of knowledge of status are higher than available self-reported HIV awareness estimates, however, suggesting - in line with previous studies - that these self-reports could be affected by nondisclosure of HIV status awareness. Conclusion: Knowledge of HIV status is a key indicator to monitor progress, identify bottlenecks, and target HIV responses. Shiny90 can help countries track progress towards their 'first 90' by leveraging surveys of HIV testing behaviors and annual HTS program data.

National HIV testing and diagnosis coverage in sub-Saharan Africa: a new modeling tool for estimating the 'first 90' from program and survey data.

OBJECTIVE: HIV testing services (HTS) are a crucial component of national HIV responses. Learning one's HIV diagnosis is the entry point to accessing life-saving antiretroviral treatment and care. Recognizing the critical role of HTS, the Joint United Nations Programme on HIV/AIDS (UNAIDS) launched the 90-90-90 targets stipulating that by 2020, 90% of people living with HIV know their status, 90% of those who know their status receive antiretroviral therapy, and 90% of those on treatment have a suppressed viral load. Countries will need to regularly monitor progress on these three indicators. Estimating the proportion of people living with HIV who know their status (i.e. the 'first 90'), however, is difficult. METHODS: We developed a mathematical model (henceforth referred to as 'Shiny90') that formally synthesizes population-based survey and HTS program data to estimate HIV status awareness over time. The proposed model uses country-specific HIV epidemic parameters from the standard UNAIDS Spectrum model to produce outputs that are consistent with other national HIV estimates. Shiny90 provides estimates of HIV testing history, diagnosis rates, and knowledge of HIV status by age and sex. We validate Shiny90 using both in-sample comparisons and out-of-sample predictions using data from three countries: Côte d'Ivoire, Malawi, and Mozambique. RESULTS: In-sample comparisons suggest that Shiny90 can accurately reproduce longitudinal sex-specific trends in HIV testing. Out-of-sample predictions of the fraction of people living with HIV ever tested over a 4-to-6-year time horizon are also in good agreement with empirical survey estimates. Importantly, out-of-sample predictions of HIV knowledge of status are consistent (i.e. within 4% points) with those of the fully calibrated model in the three countries when HTS program data are included. The model's predictions of knowledge of status are higher than available self-reported HIV awareness estimates, however, suggesting - in line with previous studies - that these self-reports could be affected by nondisclosure of HIV status awareness. CONCLUSION: Knowledge of HIV status is a key indicator to monitor progress, identify bottlenecks, and target HIV responses. Shiny90 can help countries track progress towards their 'first 90' by leveraging surveys of HIV testing behaviors and annual HTS program data.

Comparative Effectiveness and Safety of Direct Oral Anticoagulants in Patients with Atrial Fibrillation: A Systematic Review and Meta-Analysis of Observational Studies.

BACKGROUND: There are no head-to-head randomized controlled trials comparing different direct oral anticoagulants (DOACs). Thus, we systematically reviewed and meta-analyzed observational studies assessing the comparative effectiveness and safety of DOACs for stroke prevention in patients with atrial fibrillation (AF). METHODS: We systematically searched MEDLINE and EMBASE up to February 2019 for observational studies comparing different DOACs head-to-head in patients with AF. Two independent reviewers identified studies, extracted data, and assessed the risk of bias using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. Random-effects models were used to meta-analyze data across higher-quality studies. RESULTS: We identified 25 cohort studies including 1,079,565 patients with AF treated with DOACs. Meta-analysis of the 19 studies at moderate risk of bias yielded a similar risk of ischemic stroke for rivaroxaban versus dabigatran (six studies; hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.83-1.04; I2: 0%), apixaban versus dabigatran (five studies; HR 0.94; 95% CI 0.82-1.09; I2: 0%), and apixaban versus rivaroxaban (four studies; HR 1.07; 95% CI 0.93-1.23; I2: 0%). Regarding major bleeding, there was an increased risk for rivaroxaban versus dabigatran (six studies; HR 1.33; 95% CI 1.20-1.47; I2: 22%) and decreased risks for apixaban versus either dabigatran (eight studies; HR 0.71; 95% CI 0.64-0.78; I2: 0%) or rivaroxaban (eight studies; HR 0.56; 95% CI 0.48-0.65; I2: 69%). CONCLUSIONS: As head-to-head trials comparing different DOACs do not exist, available evidence derives exclusively from observational studies. These data suggest that while dabigatran, rivaroxaban, and apixaban have a similar effect on the risk of ischemic stroke, apixaban may be associated with a decreased risk of major bleeding compared with either dabigatran or rivaroxaban.

Cardiovascular Disease-Related Morbidity and Mortality in Women With a History of Pregnancy Complications.

BACKGROUND: Women with a history of certain pregnancy complications are at higher risk for cardiovascular (CVD) disease. However, most clinical guidelines only recommend postpartum follow-up of those with a history of preeclampsia, gestational diabetes mellitus, or preterm birth. This systematic review was undertaken to determine if there is an association between a broader array of pregnancy complications and the future risk of CVD. METHODS: We systematically searched PubMed, MEDLINE and EMBASE (via Ovid), CINAHL, and the Cochrane Library from inception to September 22, 2017, for observational studies of the association between the hypertensive disorders of pregnancy, placental abruption, preterm birth, gestational diabetes mellitus, low birth weight, small-for-gestational-age birth, stillbirth, and miscarriage and subsequent CVD. Likelihood ratio meta-analyses were performed to generate pooled odds ratios (OR) and 95% intrinsic confidence intervals (ICI). RESULTS: Our systematic review included 84 studies (28 993 438 patients). Sample sizes varied from 250 to 2 000 000, with a median follow-up of 7.5 years postpartum. The risk of CVD was highest in women with gestational hypertension (OR 1.7; 95% ICI, 1.3-2.2), preeclampsia (OR 2.7; 95% ICI, 2.5-3.0), placental abruption (OR 1.8; 95% ICI, 1.4-2.3), preterm birth (OR 1.6; 95% ICI, 1.4-1.9), gestational diabetes mellitus (OR 1.7; 95% ICI, 1.1-2.5), and stillbirth (OR 1.5; 95% ICI, 1.1-2.1). A consistent trend was seen for low birth weight and small-for-gestational-age birth weight but not for miscarriage. CONCLUSIONS: Women with a broader array of pregnancy complications, including placental abruption and stillbirth, are at increased risk of future CVD. The findings support the need for assessment and risk factor management beyond the postpartum period.