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.

COVID-19 vaccine immunogenicity and safety surrounding fourth and subsequent vaccine doses in patients with hematologic malignancies.

BACKGROUND: Immune response to COVID-19 vaccine is diminished in patients with hematologic malignancy. There is limited data regarding response to vaccine doses in these patients. PURPOSE: To quantify the humoral immune response engendered by 4th and subsequent doses of SARS-CoV-2 vaccination as measured by anti-Spike (anti-S) antibody levels, based on dried blood spot (DBS) testing, in patients with hematologic malignancies. Anti-S binds to the spike protein of the SARS-CoV-2 virus and is indicative of vaccine immunogenicity. METHODS: We conducted a prospective study of hematologic malignancies between August 2021 and January 2023 at 12 sites across Canada. Participants were followed longitudinally and submitted finger-prick DBS cards at set intervals associated with vaccination. Samples were processed via high throughput ELISA assay to detect serum antibodies against nucleocapsid (N) and spike (S) proteins. RESULTS: We obtained 3071 samples on 790 unique patients. Of these, 372 unique participants with 1840 samples had anti-S results available post-4th, 5th or 6th COVID-19 vaccine dose and were included for analysis. Three hundred thirty-three patients of the 372 participants submitted a DBS sample post 4th dose. Of these, 257 patients (77.2%) had a positive anti-S antibody. A total of 198 patients had paired samples pre- and post-dose 4, of which 59 (29.7%) had a negative anti-S antibody pre-dose 4. Of these, 20 (33.4%) developed positive anti-S antibody post-dose 4. One hundred forty-nine patients submitted a DBS sample post-dose 5. Of these, 135 patients (90.6%) had positive anti-S antibody. A total of 52 had paired samples pre- and post-dose 5. Six (8.7%) had a negative anti-S antibody pre-dose 5, of which two (33.3%) developed positive anti-S antibody post-dose 5. Of these 372 patients, 123 (34%) reported COVID-19 infection and 4 (1%) had a COVID-19 related hospitalization. There were no reported deaths from COVID-19. CONCLUSIONS: This prospective cohort study showed that humoral immune response improved with subsequent doses of COVID-19 vaccines.

Successes and challenges of best practice alerts to identify and engage individuals living with hepatitis C virus.

Introduction: Many individuals living with hepatitis C virus (HCV) are unaware of their diagnosis and/or have not been linked to programs providing HCV care. The use of electronic medical record (EMR) systems may assist with HCV infection identification and linkage to care. Methods: In October 2021, we implemented HCV serology-focused best practice alerts (BPAs) at The Ottawa Hospital (TOH) via our EMR (EPIC). Our BPAs were programmed to identify previously tested HCV seropositive individuals. Physicians were prompted to conduct HCV RNA testing and submit consultation requests to the TOH Viral Hepatitis Program. We evaluated data post-BPA implementation to assess the design and related outcomes. Results: From 1 September 2022 to 15 December 2022, a total of 2,029 BPAs were triggered for 139 individuals. As a consequence of the BPA prompts, nine HCV seropositive and nine HCV RNA-positive individuals were linked to care. The proportion of total consultations coming from TOH physicians increased post-BPA implementation. The BPA alerts were frequently declined, and physician engagement with our BPAs varied across specialty groups. Programming issues led to unnecessary BPA prompts (e.g., no hard stop to the prompts even though the individual was treated and cured and individuals linked to care without first undergoing HCV RNA testing). A fixed 6-month lookback period for test results limited our ability to identify many individuals. Conclusion: An EMR-based BPA can assist with the identification and engagement of HCV-infected individuals in care. However, challenges including issues with programming, time commitment toward BPA configuration, productive communication between healthcare providers and the programming team, and physician responsiveness to the BPAs require attention to optimize the impact of BPAs.

Lasting differential gene expression of circulating CD8 T cells in chronic HCV infection with cirrhosis identifies a role for Hedgehog signaling in cellular hyperfunction.

Background: The impact of chronic hepatic infection on antigen non-specific immune cells in circulation remains poorly understood. We reported lasting global hyperfunction of peripheral CD8 T cells in HCV-infected individuals with cirrhosis. Whether gene expression patterns in bulk CD8 T cells are associated with the severity of liver fibrosis in HCV infection is not known. Methods: RNA sequencing of blood CD8 T cells from treatment naïve, HCV-infected individuals with minimal (Metavir F0-1 ≤ 7.0 kPa) or advanced fibrosis or cirrhosis (F4 ≥ 12.5 kPa), before and after direct-acting antiviral therapy, was performed. CD8 T cell function was assessed by flow cytometry. Results: In CD8 T cells from pre-DAA patients with advanced compared to minimal fibrosis, Gene Ontology analysis and Gene Set Enrichment Analysis identified differential gene expression related to cellular function and metabolism, including upregulated Hedgehog (Hh) signaling, IFN-α, -γ, TGF-ß response genes, apoptosis, apical surface pathways, phospholipase signaling, phosphatidyl-choline/inositol activity, and second-messenger-mediated signaling. In contrast, genes in pathways associated with nuclear processes, RNA transport, cytoskeletal dynamics, cMyc/E2F regulation, oxidative phosphorylation, and mTOR signaling, were reduced. Hh signaling pathway was the top featured gene set upregulated in cirrhotics, wherein hallmark genes GLI1 and PTCH1 ranked highly. Inhibition of Smo-dependent Hh signaling ablated the expression of IFN-γ and perforin in stimulated CD8 T cells from chronic HCV-infected patients with advanced compared to minimal fibrosis. CD8 T cell gene expression profiles post-DAA remained clustered with pre-DAA profiles and disparately between advanced and minimal fibrosis, suggesting a persistent perturbation of gene expression long after viral clearance. Conclusions: This analysis of bulk CD8 T cell gene expression in chronic HCV infection suggests considerable reprogramming of the CD8 T cell pool in the cirrhotic state. Increased Hh signaling in cirrhosis may contribute to generalized CD8 T cell hyperfunction observed in chronic HCV infection. Understanding the lasting nature of immune cell dysfunction may help mitigate remaining clinical challenges after HCV clearance and more generally, improve long term outcomes for individuals with severe liver disease.

Frequent Disengagement and Subsequent Mortality Among People With HIV and Hepatitis C in Canada: A Prospective Cohort Study.

Background: The cascade of care, commonly used to assess HIV and hepatitis C (HCV) health service delivery, has limitations in capturing the complexity of individuals' engagement patterns. This study examines the dynamic nature of engagement and mortality trajectories among people with HIV and HCV. Methods: We used data from the Canadian HIV-HCV Co-Infection Cohort, which prospectively follows 2098 participants from 18 centers biannually. Markov multistate models were used to evaluate sociodemographic and clinical factors associated with transitioning between the following states: (1) lost-to-follow-up (LTFU), defined as no visit for 18 months; (2) reengaged (reentry into cohort after being LTFU); (3) withdrawn from the study (ie, moved); (4) death; otherwise remained (5) engaged-in-care. Results: A total of 1809 participants met the eligibility criteria and contributed 12 591 person-years from 2003 to 2022. LTFU was common, with 46% experiencing at least 1 episode, of whom only 57% reengaged. One in 5 (n = 383) participants died during the study. Participants who transitioned to LTFU were twice as likely to die as those who were consistently engaged. Factors associated with transitioning to LTFU included detectable HCV RNA (adjusted hazards ratio [aHR], 1.37; 95% confidence interval [CI], 1.13-1.67), evidence of HCV treatment but no sustained virologic response result (aHR, 1.99; 95% CI, 1.56-2.53), and recent incarceration (aHR, 1.94; 95% CI, 1.58-2.40). Being Indigenous was a significant predictor of death across all engagement trajectories. Interpretation: Disengagement from clinical care was common and resulted in higher death rates. People LTFU were more likely to require HCV treatment highlighting a priority population for elimination strategies.

Correlates of Breakthrough SARS-CoV-2 Infections in People with HIV: Results from the CIHR CTN 328 Study.

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.

Clinical and serological predictors of post COVID-19 condition-findings from a Canadian prospective cohort study.

Introduction: More than 3 years into the pandemic, there is persisting uncertainty as to the etiology, biomarkers, and risk factors of Post COVID-19 Condition (PCC). Serological research data remain a largely untapped resource. Few studies have investigated the potential relationships between post-acute serology and PCC, while accounting for clinical covariates. Methods: We compared clinical and serological predictors among COVID-19 survivors with (n = 102 cases) and without (n = 122 controls) persistent symptoms ≥12 weeks post-infection. We selected four primary serological predictors (anti-nucleocapsid (N), anti-Spike, and anti-receptor binding domain (RBD) IgG titres, and neutralization efficiency), and specified clinical covariates a priori. Results: Similar proportions of PCC-cases (66.7%, n = 68) and infected-controls (71.3%, n = 87) tested positive for anti-N IgG. More cases tested positive for anti-Spike (94.1%, n = 96) and anti-RBD (95.1%, n = 97) IgG, as compared with controls (anti-Spike: 89.3%, n = 109; anti-RBD: 84.4%, n = 103). Similar trends were observed among unvaccinated participants. Effects of IgG titres on PCC status were non-significant in univariate and multivariate analyses. Adjusting for age and sex, PCC-cases were more likely to be efficient neutralizers (OR 2.2, 95% CI 1.11-4.49), and odds was further increased among cases to report deterioration in quality of life (OR 3.4, 95% CI 1.64-7.31). Clinical covariates found to be significantly related to PCC included obesity (OR 2.3, p = 0.02), number of months post COVID-19 (OR 1.1, p < 0.01), allergies (OR 1.8, p = 0.04), and need for medical support (OR 4.1, p < 0.01). Conclusion: Despite past COVID-19 infection, approximately one third of PCC-cases and infected-controls were seronegative for anti-N IgG. Findings suggest higher neutralization efficiency among cases as compared with controls, and that this relationship is stronger among cases with more severe PCC. Cases also required more medical support for COVID-19 symptoms, and described complex, ongoing health sequelae. More data from larger cohorts are needed to substantiate results, permit subgroup analyses of IgG titres, and explore for differences between clusters of PCC symptoms. Future assessment of IgG subtypes may also elucidate new findings.

Comparable safety and non-inferior immunogenicity of the SARS-CoV-2 mRNA vaccine candidate PTX-COVID19-B and BNT162b2 in a phase 2 randomized, observer-blinded study.

In the aftermath of the COVID-19 pandemic, the evolution of the SARS-CoV-2 into a seasonal pathogen along with the emergence of new variants, underscores the need for dynamic and adaptable responses, emphasizing the importance of sustained vaccination strategies. This observer-blind, double-dummy, randomized immunobridging phase 2 study (NCT05175742) aimed to compare the immunogenicity induced by two doses of 40 µg PTX-COVID19-B vaccine candidate administered 28 days apart, with the response induced by two doses of 30 µg Pfizer-BioNTech COVID-19 vaccine (BNT162b2), administered 21 days apart, in Nucleocapsid-protein seronegative adults 18-64 years of age. Both vaccines were administrated via intramuscular injection in the deltoid muscle. Two weeks after the second dose, the neutralizing antibody (NAb) geometric mean titer ratio and seroconversion rate met the non-inferiority criteria, successfully achieving the primary immunogenicity endpoints of the study. PTX-COVID19-B demonstrated similar safety and tolerability profile to BNT162b2 vaccine. The lowest NAb response was observed in subjects with low-to-undetectable NAb at baseline or no reported breakthrough infection. Conversely, participants who experienced breakthrough infections during the study exhibited higher NAb titers. This study also shows induction of cell-mediated immune (CMI) responses by PTX-COVID19-B. In conclusion, the vaccine candidate PTX-COVID19-B demonstrated favourable safety profile along with immunogenicity similar to the active comparator BNT162b2 vaccine.

Hepatitis B Virus Genotype Influence on Virological and Enzymatic Measures over Time-A Retrospective Longitudinal Cohort Study.

HBV is a hepatotropic virus with multiple genotypes. It is uncertain if specific genotype(s) influence virological measures and/or liver markers over time. It is unclear whether nucleos(t)ide analogue therapy response is influenced by genotype. In this retrospective longitudinal study, we utilized data from The Ottawa Hospital Viral Hepatitis Program (TOHVHP) to evaluate the role of HBV genotype on viral load, liver enzymatic levels, fibrosis progression, and parenchymal inflammation and steatosis over time. HBV DNA, ALT, and AST levels, as well as transient elastography scores for fibrosis (E) and inflammation/steatosis (CAP), were modeled using mixed-effects linear regression. Interaction terms between HBV genotype and time were included to investigate if there was a difference in trends between genotypes. A total of 393 HBV patients infected with genotypes A-E were included. The mean age was 44.4 years, and 56% were male. Asian (50.5%), Black (29.1%), and White (6.4%) patients were well-represented. By multivariate analysis, we found no evidence that the trajectories of these commonly measured viral or liver measures varied over time by HBV genotype in those receiving HBV nucleos(t)ides and in those not on antiviral therapy.

Diagnosis of esophageal varices by liver stiffness and serum biomarkers in virus-related compensated advanced chronic liver disease.

Background: Individuals infected with hepatitis B (HBV), hepatitis C (HCV), and human immunodeficiency (HIV) viruses can experience compensated advanced chronic liver disease (cACLD) leading to esophageal varices (EV). In patients at low risk of esophageal varices needing treatment (EVNT), non-invasive criteria based on liver stiffness measurement (LSM) with platelets, or fibrosis biomarkers, may avoid unnecessary screening esophagogastroduodenoscopies (EGD). These approaches have not been compared among people infected with HIV, HBV, and HCV patients. Methods: Patients with a diagnosis of cACLD (LSM ≥10 kPa) and EGD availability were included from two cohorts. Baveno VI and expanded Baveno VI criteria (based on LSM and platelets), fibrosis biomarkers Fibrosis-4 Index (FIB-4), AST-to-Platelets Ratio Index (APRI), AST-to-ALT ratio (AAR), and RESIST criteria (based on platelets and albumin) were applied to determine the proportion of spared EGD and of missed EVNT. Results: Three hundred fifty three patients (30.6% with HIV, 25.3% monoinfected with HBV, and 44.1% with HCV) were included. The prevalence of EVNT was 8.2%. Both Baveno VI and expanded Baveno VI criteria performed well in patients with virus-related cACLD, by sparing 26.1% and 51.6% EGD, respectively, while missing <2% EVNT. The proportion of spared EGD were 48.2%, 58%, and 24.3% by FIB-4 (<2.78), APRI (<1.1), and AAR (<0.75), respectively, while missing <3% EVNT. RESIST criteria spared 47.8% EGD while missing 1.9% EVNT. Conclusions: Non-invasive criteria based on LSM can spare unnecessary EGD in virus-related cACLD. Simple fibrosis biomarkers can ameliorate resource utilization for EVNT screening in low resource settings.

Hepatitis B virus genotypes influence clinical outcomes: A review.

Hepatitis B virus (HBV) is a hepatotropic virus that affects approximately 296 million people worldwide. A crucial step to HBV replication is the transcription of its infectious DNA from its viral RNA intermediate. The production of the RNA intermediate hinges on reverse transcription, and therefore the lack of proofreading in that process commonly yields mutants and has led to nine well-described genotypes (A-I) and over 30 known sub-genotypes of the virus. The influence of genotype on HBV infection outcomes, which include fibrosis progression, cirrhosis, and hepatocellular carcinoma (HCC), remain uncertain. This review aims to analyze the influence of HBV genotype on the risk of development of these outcomes. The response to current and future HBV therapies is considered. Further study of larger and more diverse samples will hopefully resolve outstanding uncertainties.

Continuous false positive results by SARS-CoV-2 rapid antigen testing: a case report.

Efficient and rapid identification of active SARS-CoV-2 infections has been key to monitoring and mitigating the spread of the virus. The implementation of nucleic acid testing (e.g., RT-PCR) was broadly adopted by most public health organizations at the national and community levels across the globe, which was followed by more accessible means of home testing including lateral flow immunochromatographic assay (LFA), also known as a rapid antigen test. Here we report the case of an adult female who repeatedly and consecutively tested positive by RAT (BTNX inc). This sustained false positive was not linked with an active SARS-CoV-2 infection, which was ruled out by RT-PCR and serological analyses. SARS-CoV-2 serology revealed no detectable levels of antibodies against the nucleocapsid suggesting no recent prior infection by SARS-CoV-2. This continuous false positive was limited to BTNX testing devices. This case report aims to describe that such continuous false positives can occur and describes alternative testing approaches that can be performed to confirm RAT results. In addition, broader awareness of such occurrences is warranted in the healthcare and public health community to avoid unnecessary negative impacts on individual's day to day life.

Preventative behaviours and COVID-19 infection in a Canadian cohort of people living with HIV.

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.

COVID-19 vaccine effectiveness by HIV status and history of injection drug use: a test-negative analysis.

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.

Results of the Stop the Spread Ottawa (SSO) cohort study: a Canadian urban-based prospective evaluation of antibody responses and neutralisation efficiency to SARS-CoV-2 infection and vaccination.

BACKGROUND: Predictors of COVID-19 vaccine immunogenicity and the influence of prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection require elucidation. METHODS: Stop the Spread Ottawa is a prospective cohort of individuals at-risk for or who have been infected with SARS-CoV-2, initially enrolled for 10 months beginning October 2020. This cohort was enriched for public-facing workers. This analysis focuses on safety and immunogenicity of the initial two doses of COVID-19 vaccine. RESULTS: Post-vaccination data with blood specimens were available for 930 participants. 22.8% were SARS-CoV2 infected prior to the first vaccine dose. Cohort characteristics include: median age 44 (IQR: 22-56), 66.6% women, 89.0% white, 83.2% employed. 38.1% reported two or more comorbidities and 30.8% reported immune compromising condition(s). Over 95% had detectable IgG levels against the spike and receptor binding domain (RBD) 3 months post second vaccine dose. By multivariable analysis, increasing age and high-level immune compromise predicted diminishing IgG spike and RBD titres at month 3 post second dose. IgG spike and RBD titres were higher immediately post vaccination in those with SARS-CoV-2 infection prior to first vaccination and spike titres were higher at 6 months in those with wider time intervals between dose 1 and 2. IgG spike and RBD titres and neutralisation were generally similar by sex, weight and whether receiving homogeneous or heterogeneous combinations of vaccines. Common symptoms post dose 1 vaccine included fatigue (64.7%), injection site pain (47.5%), headache (27.2%), fever/chills (26.2%) and body aches (25.3%). These symptoms were similar with subsequent doses. CONCLUSION: The initial two COVID-19 vaccine doses are safe, well-tolerated and highly immunogenic across a broad spectrum of vaccine recipients including those working in public facing environments.

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.

Protocol for a living evidence synthesis on variants of concern and COVID-19 vaccine effectiveness.

BACKGROUND: It is evident that COVID-19 will remain a public health concern in the coming years, largely driven by variants of concern (VOC). It is critical to continuously monitor vaccine effectiveness as new variants emerge and new vaccines and/or boosters are developed. Systematic surveillance of the scientific evidence base is necessary to inform public health action and identify key uncertainties. Evidence syntheses may also be used to populate models to fill in research gaps and help to prepare for future public health crises. This protocol outlines the rationale and methods for a living evidence synthesis of the effectiveness of COVID-19 vaccines in reducing the morbidity and mortality associated with, and transmission of, VOC of SARS-CoV-2. METHODS: Living evidence syntheses of vaccine effectiveness will be carried out over one year for (1) a range of potential outcomes in the index individual associated with VOC (pathogenesis); and (2) transmission of VOC. The literature search will be conducted up to May 2023. Observational and database-linkage primary studies will be included, as well as RCTs. Information sources include electronic databases (MEDLINE; Embase; Cochrane, L*OVE; the CNKI and Wangfang platforms), pre-print servers (medRxiv, BiorXiv), and online repositories of grey literature. Title and abstract and full-text screening will be performed by two reviewers using a liberal accelerated method. Data extraction and risk of bias assessment will be completed by one reviewer with verification of the assessment by a second reviewer. Results from included studies will be pooled via random effects meta-analysis when appropriate, or otherwise summarized narratively. DISCUSSION: Evidence generated from our living evidence synthesis will be used to inform policy making, modelling, and prioritization of future research on the effectiveness of COVID-19 vaccines against VOC.

Antibody neutralization capacity after coronavirus disease 2019 vaccination in people with HIV in Canada.

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.

Role of fatty liver in the epidemic of advanced chronic liver disease among people with HIV: protocol for the Canadian LIVEHIV multicentre prospective cohort.

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.

Public reimbursement policies in Canada for direct-acting antiviral treatment of hepatitis C virus infection: A descriptive study.

Background: Direct-acting antiviral (DAA) therapies have simplified HCV treatment, and publicly funded Canadian drug plans have eliminated disease-stage restrictions for reimbursement of DAA therapies. However other policies which complicate, delay, or prevent treatment initiation still persist. We aim to describe these plans' existing reimbursement criteria and appraise whether they hinder treatment access. Methods: We reviewed DAA reimbursement policies of 16 publicly funded drug plans published online and provided by contacts with in-depth knowledge of prescribing criteria. Data were collected from May to July 2022. Primary outcomes were: (1) if plans have arranged to accept point-of-care HCV RNA testing for diagnosis; testing requirements for (2) HCV genotype, (3) fibrosis stage, and (4) chronic infection; (5) time taken and method used to approve reimbursement requests; (6) providers eligible to prescribe DAAs; and (7) restrictions on re-treatment. Results: Fifteen (94%) plans have at least one policy in place which limits simplified HCV treatment. Many plans continue to require results of genotype or fibrosis staging, limit eligible prescribers, and take longer than 1 day to approve coverage requests. One plan discourages treatment for re-infection. Conclusion: Reimbursement criteria set by publicly funded Canadian drug plans continue to limit timely, equitable access to HCV treatment. Eliminating clinically irrelevant pre-authorization testing, expanding eligible prescribers, expediting claims processing, and broadening coverage of treatment for reinfection will improve access to DAAs. The federal government could further enhance efforts by introducing a federal HCV elimination strategy or federal high-cost drug PharmaCare program.