Real-world evidence of sotrovimab effectiveness for preventing severe outcomes in patients with COVID-19: A quality improvement propensity matched retrospective cohort study of a pan-provincial program in Alberta, Canada.

OBJECTIVE: Post-marketing surveillance of sotrovimab's effect during implementation in the Canadian population is limited. METHODS: The study used a propensity score matched retrospective cohort design. Follow-up began between the periods of December 15, 2021 to April 30 2022. The study assessed any severe outcome defined as all-cause hospital admission, or mortality within 30 days of a confirmed COVID-19 positive test. Covariate adjusted odds ratios between sotrovimab treatment and the severe outcome was conducted using logistic regression. RESULTS: There were 22,289 individuals meeting treatment criteria for sotrovimab. There were 1,603 treated and 6,299 untreated individuals included in the analysis. Outcome occurrence in the study was 5.49% (treated) and 4.21% (untreated), with a median time from diagnosis to treatment of 1.00 days (IQR = 2.00 days). In the propensity-matched cohort, sotrovimab was not associated with a lower odds of a severe outcome (OR = 1.20; 95% CI: 0.91, 1.58), adjusting for confounding variables. CONCLUSION: After adjusting for confounding variables, sotrovimab treatment was not associated with lower odds of a severe outcome within 30-days of COVID-19 positive date.

Cytomegalovirus surveillance after antiviral prophylaxis in CMV mismatched transplant patients: Does recurrent cytomegalovirus DNAemia impact patient survival?

BACKGROUND: Cytomegalovirus (CMV) mismatched, donor IgG-positive/recipient IgG-negative, solid organ transplant recipients (SOTRs) are at high risk of CMV invasive disease. Post-prophylaxis disease is an issue in this population. Some programs employ surveillance after prophylaxis (SAP) to limit the incidence of post-prophylaxis disease. METHODS: This was a single-center retrospective cohort study that included all CMV mismatched SOTRs from 2003 to 2017. Patients underwent SAP with weekly CMV plasma viral load for 12 weeks. The subjects were classified into three post-prophylaxis DNAemia patterns: no DNAemia, one episode of DNAemia, and multiple episodes of DNAemia. We calculated the cumulative incidence of each DNAemia pattern. We also determined 5-year mortality based on DNAemia pattern stratified by organ transplant type. RESULTS: Post-prophylaxis recurrent DNAemia occurred in 63% of lung recipients and 32% of non-lung recipients (p =  .003). Tissue invasive CMV disease was diagnosed in 3% of the population and CMV syndrome was diagnosed in 33%. Recurrent DNAemia was not associated with 5-year mortality. CONCLUSION: In this cohort, undergoing SAP tissue invasive disease was uncommon and CMV DNAemia recurrence did not have an impact on long-term mortality.

Porcine-derived pancreatic enzyme replacement therapy may be linked to chronic hepatitis E virus infection in cystic fibrosis lung transplant recipients.

OBJECTIVES: In high-income countries hepatitis E virus (HEV) is an uncommonly diagnosed porcine-derived zoonoses. After identifying disproportionate chronic HEV infections in persons with cystic fibrosis (pwCF) postlung transplant, we sought to understand its epidemiology and potential drivers. DESIGN: All pwCF post-transplant attending our regional CF centre were screened for HEV. HEV prevalence was compared against non-transplanted pwCF and with all persons screened for suspected HEV infection from 2016 to 2022 in Alberta, Canada. Those with chronic HEV infection underwent genomic sequencing and phylogenetic analysis. Owing to their swine derivation, independently sourced pancreatic enzyme replacement therapy (PERT) capsules were screened for HEV. RESULTS: HEV seropositivity was similar between transplanted and non-transplanted pwCF (6/29 (21%) vs 16/83 (19%); p=0.89). Relative to all other Albertans investigated for HEV as a cause of hepatitis (n=115/1079, 10.7%), pwCF had a twofold higher seropositivity relative risk and this was four times higher than the Canadian average. Only three chronic HEV infection cases were identified in all of Alberta, all in CF lung transplant recipients (n=3/29, 10.3%). Phylogenetics confirmed cases were unrelated porcine-derived HEV genotype 3a. Ninety-one per cent of pwCF were taking PERT (median 8760 capsules/person/year). HEV RNA was detected by RT-qPCR in 44% (47/107) of PERT capsules, and sequences clustered with chronic HEV cases. CONCLUSION: PwCF had disproportionate rates of HEV seropositivity, regardless of transplant status. Chronic HEV infection was evident only in CF transplant recipients. HEV may represent a significant risk for pwCF, particularly post-transplant. Studies to assess HEV incidence and prevalence in pwCF, and potential role of PERT are required.

The impact of colonization by multidrug resistant bacteria on graft survival, risk of infection, and mortality in recipients of solid organ transplant: systematic review and meta-analysis.

BACKGROUND: The Global increase in colonization by multidrug-resistant (MDR) bacteria poses a significant concern. The precise impact of MDR colonization in solid organ transplant recipients (SOTR) remains not well established. OBJECTIVES: To assess the impact of MDR colonization on SOTR's mortality, infection, or graft loss. METHODS AND DATA SOURCES: Data from PROSPERO, OVID Medline, OVID EMBASE, Wiley Cochrane Library, ProQuest Dissertations, Theses Global, and SCOPUS were systematically reviewed, spanning from inception until 20 March 2023. The study protocol was registered with PROSPERO (CRD42022290011) and followed the PRISMA guidelines. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, INTERVENTIONS, AND ASSESSMENT OF RISK OF BIAS: Cohorts and case-control studies that reported on adult SOTR colonized by Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), extended-spectrum ß-lactamase (ESBL) or carbapenem-resistant Enterobacteriaceae. (CRE), or MDR-pseudomonas, and compared to noncolonized, were included. Two reviewers assessed eligibility, conducted a risk of bias evaluation using the Newcastle-Ottawa Scale, and rated certainty of evidence using the GRADE approach. METHODS OF DATA SYNTHESIS: We employed RevMan for a meta-analysis, using random-effects models to compute pooled odds ratios (OR) and 95% confidence intervals (CI). Statistical heterogeneity was determined using the I2 statistic. RESULTS: 15,202 SOTR (33 cohort, six case-control studies) were included, where liver transplant and VRE colonization (25 and 14 studies) were predominant. MDR colonization significantly increased posttransplant 1-year mortality (OR, 2.35; 95% CI, 1.63-3.38) and mixed infections (OR, 10.74; 95% CI, 7.56-12.26) across transplant types (p < 0.001 and I2 = 58%), but no detected impact on graft loss (p 0.41, I2 = 0). Subgroup analysis indicated a higher association between CRE or ESBL colonization with outcomes (CRE: death OR, 3.94; mixed infections OR, 24.8; ESBL: mixed infections OR, 10.3; no mortality data) compared to MRSA (Death: OR, 2.25; mixed infection: OR, 7.75) or VRE colonization (Death: p 0.20, mixed infections: OR, 5.71). CONCLUSIONS: MDR colonization in SOTR, particularly CRE, is associated with increased mortality. Despite the low certainty of the evidence, actions to prevent MDR colonization in transplant candidates are warranted.

Sexual and gender minority relevant policies in Canadian and United States organ and tissue donation and transplantation systems: An opportunity to improve equity and safety.

Current policies in organ and tissue donation and transplantation (OTDT) systems in Canada and the United States unnecessarily restrict access to donation for sexual and gender minorities (SGMs) and pose safety risks to transplant recipients. We compare SGM-relevant policies between the Canadian and United States systems. Policy domains include the risk assessment of living and deceased organ and tissue donors, physical examination considerations, viral testing recommendations, and informed consent and communication. Identified gaps between current evidence and existing OTDT policies along with differences in SGM-relevant policies between systems, represent an opportunity for improvement. Specific recommendations for OTDT system policy revisions to achieve these goals include the development of behavior-based, gender-neutral risk assessment criteria, a reduction in current SGM no-sexual contact period requirements pending development of inclusive criteria, and destigmatization of sexual contact with people living with human immunodeficiency virus. OTDT systems should avoid rectal examinations to screen for evidence of receptive anal sex without consent and mandate routine nucleic acid amplification test screening for all donors. Transplant recipients must receive enhanced risk-to-benefit discussions regarding decisions to accept or decline an offer of an organ classified as increased risk. These recommendations will expand the donor pool, enhance equity for SGM people, and improve safety and outcomes for transplant recipients.

How does the antimicrobial stewardship provider role affect prospective audit and feedback acceptance for restricted antibiotics in a Canadian tertiary-care center?

Of 731 restricted antimicrobial prescriptions subject to antimicrobial stewardship program (ASP) prospective audit and feedback (PAF) over a 3-year period, 598 PAF recommendations (82%) were fully accepted. Physician auditors had an increased odds of PAF recommendation acceptance, reinforcing the complementary role of the ASP physician in the multidisciplinary ASP team.

Systemic corticosteroids for outpatient respiratory viral infections in lung transplant recipients.

INTRODUCTION: Respiratory viral infections (RVI) in lung transplant recipients (LTR) have variably been associated with rejection and chronic lung allograft dysfunction. Our center has used systemic corticosteroids to treat outpatient RVI in some cases, but evidence is limited. We reviewed all adult LTR diagnosed with outpatient RVI January 2017 to December 2019. The primary outcome was recovery of lung function (forced expiratory volume in 1 s [FEV1]) at next stable visit between 1 and 12 months postinfection, expressed as a ratio over stable preinfection FEV1 (FEV1 recovery ratio). METHODS: We identified 100 adult LTR with outpatient RVI diagnoses eligible for study, 36% of whom received corticosteroids. We modelled the adjusted association between corticosteroid use and FEV1 recovery ratio using linear regression. RESULTS: Steroid-treated patients had a lower FEV1 presentation ratio (0.92 vs. 1.04, p = .0070) and were more likely to have chronic lung allograft dysfunction at time of infection (25% vs. 5%, p = .0077). Mean FEV1 recovery ratio was 1.02 (SD 0.19) with no association with corticosteroid therapy via multivariable linear regression (p = .5888). CONCLUSIONS: Steroid treatment was not associated with FEV1 recovery. This suggests corticosteroids may not have a role in the management of RVI in this population.

Evaluation and comparison of risk-based and universal prenatal HCV screening programs in Alberta, Canada.

BACKGROUND & AIMS: Canadian clinical practice guidelines currently recommend risk-based screening for HCV in pregnant individuals. However, no provinces or territories have ever compared the effectiveness of risk-based vs. universal screening for the prenatal diagnosis of HCV. We aimed to evaluate and compare HCV screening programs after implementing a universal population-level pilot program among prenatal patients in Alberta, Canada. METHODS: The Alberta Prenatal Screening Program for Select Communicable Diseases was amended to include universal HCV antibody screening. Cohorts of pregnant individuals screened for HCV through risk-based or universal programs were generated over 1-year periods. HCV screening rates and prevalence were analyzed and compared between cohorts to evaluate the effectiveness of screening methods. Social and demographic risk factors for HCV-positive individuals were compared between screening cohorts to identify which populations may be overlooked with risk-based guidelines. RESULTS: HCV antibody screening rates were 11.9% and 99.9% among pregnant individuals in the risk-based and universal cohorts, respectively. HCV prevalence among the cohorts was 0.07% and 0.11% (difference = 0.04%, p = 0.032), with an average of 21 additional HCV-positive pregnant individuals identified annually with universal screening. HCV-positive pregnant patients diagnosed through universal screening were more likely to engage in high-risk sexual behaviours/sex work compared to those diagnosed through risk-based screening (47.6% vs. 12.5%, respectively p = 0.035), suggesting that these high-risk cases are being missed by risk-based screening. CONCLUSIONS: Universal HCV screening diagnoses significantly higher numbers of pregnant individuals infected with HCV compared to risk-based screening. Universal HCV screening or amending risk-based guidelines to incorporate more proxy variables for risk factors should be considered to improve prenatal HCV screening guidelines in Canada and help achieve HCV elimination in the next decade. IMPACT AND IMPLICATIONS: HCV is a bloodborne pathogen that can cause severe liver disease and be vertically transmitted from a mother to her baby during pregnancy. Pregnant individuals in Alberta are currently only tested for HCV if they disclose engaging in activities that put them at risk of acquiring the infection (risk-based screening). Using a population-wide universal prenatal HCV screening program, our work shows that testing based on patient disclosed risk alone leads to the significant underdiagnosis of HCV in pregnant individuals and suggests individuals engaging in sex work or risky sexual behaviours are being overlooked by the current risk-based program. Our outcomes represent the first province-wide study to evaluate and compare prenatal HCV risk-based and universal screening programs in Canada and provide evidence to support the update of prenatal HCV screening policies across the country and in similar jurisdictions.

Immune-Based Therapy for Hospitalized Patients With COVID-19 and Risk of Secondary Infections: A Systematic Review and Meta-analysis.

Background: Immune-based therapies are standard-of-care treatment for coronavirus disease 2019 (COVID-19) patients requiring hospitalization. However, safety concerns related to the potential risk of secondary infections may limit their use. Methods: We searched OVID Medline, Ovid EMBASE, SCOPUS, Cochrane Library, clinicaltrials.gov, and PROSPERO in October 2020 and updated the search in November 2021. We included randomized controlled trials (RCTs). Pairs of reviewers screened abstracts and full studies and extracted data in an independent manner. We used RevMan to conduct a meta-analysis using random-effects models to calculate the pooled risk ratio (RR) and 95% CI for the incidence of infection. Statistical heterogeneity was determined using the I 2 statistic. We assessed risk of bias for all studies and rated the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation methodology. We conducted a meta-regression using the R package to meta-explore whether age, sex, and invasive mechanical ventilation modified risk of infection with immune-based therapies. The protocol is registered with PROSPERO (CRD42021229406). Results: This was a meta-analysis of 37 RCTs including 32 621 participants (mean age, 60 years; 64% male). The use of immune-based therapy for COVID-19 conferred mild protection for the occurrence of secondary infections (711/15 721, 4.5%, vs 616/16 900, 3.6%; RR, 0.82; 95% CI, 0.71-0.95; P = .008; I 2 = 28%). A subgroup analysis did not identify any subgroup effect by type of immune-based therapies (P = .85). A meta-regression revealed no impact of age, sex, or mechanical ventilation on the effect of immune-based therapies on risk of infection. Conclusions: We identified moderate-certainty evidence that the use of immune-based therapies in COVID-19 requiring hospitalization does not increase the risk of secondary infections.

Efficacy and safety of antimicrobial stewardship prospective audit and feedback in patients hospitalised with COVID-19 (COVASP): a pragmatic, cluster-randomised, non-inferiority trial.

BACKGROUND: The COVID-19 pandemic has been associated with increased antimicrobial use despite low rates of bacterial co-infection. Prospective audit and feedback is recommended to optimise antibiotic prescribing, but high-quality evidence supporting its use for COVID-19 is absent. We aimed to study the efficacy and safety of prospective audit and feedback in patients admitted to hospital for the treatment of COVID-19. METHODS: COVASP was a prospective, pragmatic, non-inferiority, small-unit, cluster-randomised trial comparing prospective audit and feedback plus standard of care with standard of care alone in adults admitted to three hospitals in Edmonton, AB, Canada, with COVID-19 pneumonia. All patients aged at least 18 years who were admitted from the community to a designated study bed with microbiologically confirmed SARS-CoV-2 infection in the preceding 14 days were included if they had an oxygen saturation of 94% or lower on room air, required supplemental oxygen, or had chest-imaging findings compatible with COVID-19 pneumonia. Patients were excluded if they were transferred in from another acute care centre, enrolled in another clinical trial that involved antibiotic therapy, expected to progress to palliative care or death within 48 h of hospital admission, or managed by any member of the research team within 30 days of enrolment. COVID-19 unit and critical care unit beds were stratified and randomly assigned (1:1) to the prospective audit and feedback plus standard of care group or the standard of care group. Patients were masked to their bed assignment but the attending physician and study team were not. The primary outcome was clinical status on postadmission day 15, measured using a seven-point ordinal scale. We used a non-inferiority margin of 0·5. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, NCT04896866, and is now closed. FINDINGS: Between March 1 and Oct 29, 2021, 1411 patients were screened and 886 were enrolled: 457 into the prospective audit and feedback plus standard of care group, of whom 429 completed the study, and 429 into the standard of care group, of whom 404 completed the study. Baseline characteristics were similar for both groups, with an overall mean age of 56·7 years (SD 17·3) and a median baseline ordinal scale of 4·0 (IQR 4·0-5·0). 301 audit and feedback events were recorded in the intervention group and 215 recommendations were made, of which 181 (84%) were accepted. Despite lower antibiotic use in the intervention group than in the control group (length of therapy 364·9 vs 384·2 days per 1000 patient days), clinical status at postadmission day 15 was non-inferior (median ordinal score 2·0 [IQR 2·0-3·0] vs 2·0 [IQR 2·0-4·0]; p=0·37, Mann-Whitney U test). Neutropenia was uncommon in both the intervention group (13 [3%] of 420 patients) and the control group (20 [5%] of 396 patients), and acute kidney injury occurred at a similar rate in both groups (74 [18%] of 421 patients in the intervention group and 76 [19%] of 399 patients in the control group). No intervention-related deaths were recorded. INTERPRETATION: This cluster-randomised clinical trial shows that prospective audit and feedback is safe and effective in optimising and reducing antibiotic use in adults admitted to hospital with COVID-19. Despite many competing priorities during the COVID-19 pandemic, antimicrobial stewardship should remain a priority to mitigate the overuse of antibiotics in this population. FUNDING: None.

Serologic follow-up of solid organ transplant recipients who received organs from donors with reactive syphilis tests: A retrospective cohort study.

The increased procurement of organs from donors with risk factors for blood-borne diseases and the expanding syphilis epidemic have resulted in a growing number of organs transplanted from donors with reactive syphilis serology in our center. Based on guidelines, recipients typically receive therapy shortly after the transplant, but data on outcomes are limited. The primary objective of this study was to determine syphilis seroconversion rates at three months post-transplant in recipients of solid organs procured from donors with reactive syphilis serology. Organ donors and recipients were tested for syphilis antibody; positive results were confirmed with Treponema pallidum Particle Agglutination (TPPA). Eleven donors with reactive syphilis antibody donated organs to 25 syphilis negative recipients. Three recipients seroconverted at post-transplant month 3. All of them had received therapy shortly after transplant. TPPA was negative in all 3. Despite post-transplant treatment, 3 of 25 (12%) syphilis negative recipients of organs from syphilis positive donors seroconverted at 3 months. All remained TPPA negative possibly reflecting passive antibody transfer or differing test sensitivity to low level treponemal antibodies. Further studies are needed to assess optimal syphilis transmission prevention strategies and follow up recipient testing in organ transplantation.

Clinical Outcomes and Quantitative HBV Surface Antigen Levels in Diverse Chronic Hepatitis B Patients in Canada: A Retrospective Real-World Study of CHB in Canada (REVEAL-CANADA).

BACKGROUND: Hepatitis B surface antigen (HBsAg) loss is associated with improved clinical outcomes for individuals with chronic hepatitis B (CHB); however, the effects of varying HBsAg levels on clinical outcomes in diverse cohorts are understudied. METHODS: In this cross-sectional, multicentre, retrospective study, the data on adult subjects enrolled in the Canadian HBV Network with CHB seen from 1 January 2012 to 30 January 2021 with the treatment and virologic data within 1 year of HBsAg testing were analyzed. Patients were tested for HBsAg using qualitative (for HBsAg-negative samples) and/or commercial quantitative assays. Fibrosis or hepatic necroinflammation was determined by the liver stiffness measurement (LSM). The baseline data were summarized using descriptive statistics and compared by using univariable/multivariable analyses. RESULTS: This study included 844 CHB patients, with a median age of 49.6 years (IQR 40.1-60.5), and 37% were female. In total, 751 patients (78.6%) had known ethnicity data, and 76.7% self-reported as Asian, 11.4% as Black, 6.8% as White, and 4.8% as other. Among the 844 patients, 237 (28.0%) were HBsAg (-) (1000 IU/mL. Overall, 80% (682) had known HBeAg status at the last follow-up, and the majority (87.0%) were HBeAg-negative. In addition, 54% (461/844) had prior antiviral therapy, 19.7% of which (16.3, 23.7, n = 91) were HBsAg (-). The treated patients had a lower risk of cirrhosis (16.46, 95% CI 1.89-143.39, p = 0.01) or HCC (8.23, 95% CI 1.01-67.39, p = 0.05) than the untreated patients. A lower proportion of the HBsAg-loss group had cirrhosis (5.7% vs. 10.9%, p = 0.021) and HCC (0.9% vs. 6.2%, p = 0.001). CONCLUSION: In this retrospective, ethnically diverse cohort study, CHB patients who received antiviral therapy and/or had HBsAg loss were less likely to develop cirrhosis and HCC, confirming the results of the studies in less diverse cohorts. No association was found between the qHBsAg level and fibrosis determined with LSM. Individuals who achieved HBsAg loss had low-level qHBsAg within 1 year of seroclearance.

Brief Report: Effect of Antiretroviral Switch From Tenofovir Disoproxil fumarate to Tenofovir Alafenamide on Alanine Aminotransferase, Lipid Profiles, and Renal Function in HIV/HBV-Coinfected Individuals in a Nationwide Canadian Study.

OBJECTIVE: Tenofovir alafenamide (TAF) achieves increased renal safety and improved alanine aminotransferase (ALT) normalization but increased lipid profile in hepatitis B virus (HBV)-monoinfected patients switched from tenofovir disoproxil fumarate (TDF). It is unclear whether HIV coinfection perturbs these biochemical changes. To this end, we assessed these parameters in HIV/HBV-coinfected patients switched from TDF to TAF. DESIGN: Retrospective, multicenter, observational study. METHODS: HIV/HBV-coinfected patients switched from TDF to TAF-based antiretroviral therapy (ART) at 6 Canadian Hepatitis B Network (CanHepB) academic sites were included. Changes in lipid profile, estimated glomerular filtration rate (eGFR), and ALT were evaluated using linear mixed effect model regression. RESULTS: Eighty-two HIV/HBV-coinfected patients with a mean 103-week follow-up duration were identified. At time of TAF switch, 80 of 82 (98%) were HBV virally suppressed, 29 of 82 (35%) had elevated ALT levels, and 63 of 82 (77%) had eGFR of ≥60 mL/min per 1.73 m 2 . Twenty-six/Eighty-two (32%) had preexisting renal comorbidities. There were no changes in total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels 2 years after TAF switch. Those with elevated ALT levels achieved greater ALT normalization after TAF switch (-0.004 [-0.008 to 0.0] log 10 U/L/mo, P = 0.03). eGFR decline rate while on TDF (-0.66 [-0.23 to -1.08] mL/min/month, P < 0.005) was diminished after switching to TAF (-0.02 [-0.16 to 0.11] mL/min/mo, P = 0.7) and those with eGFR of <60 mL/min experienced increase in eGFR after TAF switch (0.45 [0.03-0.87] mL/min/mo, P = 0.04). CONCLUSIONS: Our study supports switching from TDF to TAF with positive influence on overall long-term biochemical profile in HIV/HBV-coinfected individuals.

Nationwide retrospective study of hepatitis B virological response and liver stiffness improvement in 465 patients on nucleos(t)ide analogue.

BACKGROUND: Hepatitis B virus (HBV) nucleos(t)ide analog (NA) therapy reduces liver disease but requires prolonged therapy to achieve hepatitis B surface antigen (HBsAg) loss. There is limited North American real-world data using non-invasive tools for fibrosis assessment and few have compared 1st generation NA or lamivudine (LAM) to tenofovir disoproxil fumarate (TDF). AIM: To assess impact of NA on virological response and fibrosis regression using liver stiffness measurement (LSM) (i.e., FibroScan®). METHODS: Retrospective, observational cohort study from the Canadian HBV Network. Data collected included demographics, NA, HBV DNA, alanine aminotransferase (ALT), and LSM. Patients were HBV monoinfected patients, treatment naïve, and received 1 NA with minimum 1 year follow-up. RESULTS: In 465 (median 49 years, 37% female, 35% hepatitis B e antigen+ at baseline, 84% Asian, 6% White, and 9% Black). Percentage of 64 (n = 299) received TDF and 166 were LAM-treated with similar median duration of 3.9 and 3.7 years, respectively. The mean baseline LSM was 11.2 kPa (TDF) vs 8.3 kPa (LAM) (P = 0.003). At 5-year follow-up, the mean LSM was 7.0 kPa in TDF vs 6.7 kPa in LAM (P = 0.83). There was a significant difference in fibrosis regression between groups (i.e., mean -4.2 kPa change in TDF and -1.6 kPa in LAM, P < 0.05). The last available data on treatment showed that all had normal ALT, but more TDF patients were virologically suppressed (< 10 IU/mL) (n = 170/190, 89%) vs LAM-treated (n = 35/58, 60%) (P < 0.05). None cleared HBsAg. CONCLUSION: In this real-world North American study, approximately 5 years of NA achieves liver fibrosis regression rarely leads to HBsAg loss.

Molecular epidemiology and clinical characteristics of hepatitis D virus infection in Canada.

Background & Aims: HDV affects 4.5-13% of chronic hepatitis B (CHB) patients globally, yet the prevalence of HDV infection in Canada is unknown. To investigate the prevalence, genotype, demographics, and clinical characteristics of HDV in Canada, we conducted a retrospective analysis of (1) HDV antibody and RNA positivity among referred specimens, and (2) a cross-sectional subset study of 135 HDV seropositive +/-RNA (HDV+) patients compared with 5,132 HBV mono-infected patients in the Canadian HBV Network. Methods: Anti-HDV IgG-positive specimens collected between 2012 and 2019 were RNA tested and the genotype determined. Patients enrolled in the Canadian HBV Network were >18 years of age and HBsAg-positive. Clinical data collected included risk factors, demographics, comorbidities, treatment, fibrosis assessment, and hepatic complications. Results: Of the referred patients, 338/7,080 (4.8%, 95% CI 4.3-5.3) were HDV seropositive, with 219/338 RNA-positive (64.8%, 95% CI 59.6-69.7). The HDV+ cohort were more likely to be born in Canada, to be White or Black/African/Caribbean than Asian, and reporting high-risk behaviours, compared with HBV mono-infected patients. Cirrhosis, complications of end-stage liver disease, and liver transplantation were significantly more frequent in the HDV+ cohort. HDV viraemia was significantly associated with elevated liver transaminases and cirrhosis. Five HDV genotypes were observed among referred patients but no association between genotype and clinical outcome was detected within the HDV+ cohort. Conclusions: Nearly 5% of the Canadian HBV referral population is HDV seropositive. HDV infection is highly associated with risk behaviours and both domestic and foreign-born patients with CHB. HDV was significantly associated with progressive liver disease highlighting the need for increased screening and surveillance of HDV in Canada. Lay summary: Evidence of HDV infection was observed in approximately 5% of Canadians who were infected with HBV referred to medical specialists. HDV-positive patients were more likely to be male, born in Canada, or White or Black/African/Caribbean compared to Asian, and to have reported high-risk activities such as injection or intranasal drug use or high-risk sexual contact compared with patients infected with only HBV. Patients infected with HDV were also more likely to suffer severe liver disease, including liver cancer, compared with HBV mono-infected patients.

Efficacy and safety of antimicrobial stewardship prospective audit and feedback in patients hospitalized with COVID-19: A protocol for a pragmatic clinical trial.

BACKGROUND: The use of broad-spectrum antibiotics is widespread in patients with COVID-19 despite a low prevalence of bacterial co-infection, raising concerns for the accelerated development of antimicrobial resistance. Antimicrobial stewardship (AMS) is vital but there are limited randomized clinical trial data supporting AMS interventions such as prospective audit and feedback (PAF). High quality data to demonstrate safety and efficacy of AMS PAF in hospitalized COVID-19 patients are needed. METHODS AND DESIGN: This is a prospective, multi-center, non-inferiority, pragmatic randomized clinical trial evaluating AMS PAF intervention plus standard of care (SOC) versus SOC alone. We include patients with microbiologically confirmed SARS-CoV-2 infection requiring hospital admission for severe COVID-19 pneumonia. Eligible ward beds and critical care unit beds will be randomized prior to study commencement at each participating site by computer-generated allocation sequence stratified by intensive care unit versus conventional ward in a 1:1 fashion. PAF intervention consists of real time review of antibacterial prescriptions and immediate written and verbal feedback to attending teams, performed by site-based AMS teams comprised of an AMS pharmacist and physician. The primary outcome is clinical status at post-admission day 15 measured using a 7-point ordinal scale. Patients will be followed for secondary outcomes out to 30 days. A total of 530 patients are needed to show a statistically significant non-inferiority, with 80% power and 2.5% one-sided alpha assuming standard deviation of 2 and the non-inferiority margin of 0.5. DISCUSSION: This study protocol presents a pragmatic clinical trial design with small unit cluster randomization for AMS intervention in hospitalized COVID-19 that will provide high-level evidence and may be adopted in other clinical situations. TRIAL REGISTRATION: This study is being performed at the University of Alberta and is registered at ClinicalTrials.gov (NCT04896866) on May 17, 2021.

Cytomegalovirus transmission in mismatched solid organ transplant recipients: Are factors other than anti-viral prophylaxis at play?

Although antiviral prophylaxis has reduced cytomegalovirus (CMV) DNAemia and disease in seronegative solid organ transplant (SOT) recipients (R-) receiving seropositive donor organs (D+), its impact on CMV transmission is uncertain. Transmission, defined as CMV antigenemia/CMV DNAemia and/or seroconversion by year 2, and associated demographic risk factors were studied retrospectively in 428 D+/R- and 429 D-/R- patients receiving a SOT at our center. The cumulative transmission incidence was higher for lung (90.5%) and liver recipients (85.1%) than heart (72.7%), kidney (63.9%), and pancreas (56.2%) recipients (p < .001) and was significantly lower in living (50.1%) versus deceased donor (77.4%, p < .001) kidney recipients despite identical antiviral prophylaxis. In multivariate analysis, only allograft type predicted transmission risk (HR [CI] lung 1.609 [1.159, 2.234] and liver 1.644 [1.209, 2.234] vs kidney). For 53 D+ donating to >1 R- with adequate follow-up, 43 transmitted to all, three transmitted to none, and seven transmitted inconsistently with lungs and livers always transmitting but donor-matched heart, kidney or kidney-pancreas allografts sometimes not. Kidney pairs transmitted concordantly. CMV transmission risk is allograft-specific and unchanged despite antiviral prophylaxis. Tracking transmission and defining donor factors associated with transmission escape may provide novel opportunities for more targeted CMV prevention and improve outcome analysis in antiviral and vaccine trials.

Mycobacteria: Selection of Transplant Candidates and Post-lung Transplant Outcomes.

Mycobacterium is a large, clinically relevant bacterial genus made up of the agents of tuberculosis and leprosy and hundreds of species of saprophytic nontuberculous mycobacteria (NTM). Pathogenicity, clinical presentation, epidemiology, and antimicrobial susceptibilities are exceptionally diverse between species. Patients with end-stage lung disease and recipients of lung transplants are at a higher risk of developing NTM colonization and disease and of severe manifestations and outcomes of tuberculosis. Data from the past three decades have increased our knowledge of these infections in lung transplant recipients. Still, there are knowledge gaps to be addressed to further our understanding of risk factors and optimal treatments for mycobacterial infections in this population.