Global Real-World Evidence of Sofosbuvir/Velpatasvir as a Highly Effective Treatment and Elimination Tool in People with Hepatitis C Infection Experiencing Mental Health Disorders.

Hepatitis C virus (HCV) is prevalent in people with mental health disorders, a priority population to diagnose and cure in order to achieve HCV elimination. This integrated analysis pooled data from 20 cohorts in seven countries to evaluate the real-world effectiveness of the pangenotypic direct-acting antiviral (DAA) sofosbuvir/velpatasvir (SOF/VEL) in people with mental health disorders. HCV-infected patients diagnosed with mental health disorders who were treated with SOF/VEL for 12 weeks without ribavirin as part of routine clinical practice were included. The primary outcome was sustained virological response (SVR) in the effectiveness population (EP), defined as patients with an available SVR assessment. Secondary outcomes were reasons for not achieving SVR, characteristics of patients with non-virological failures, adherence, and time from HCV RNA diagnosis to SOF/VEL treatment initiation. A total of 1209 patients were included; 142 did not achieve an SVR for non-virological reasons (n = 112; 83 lost to follow-up, 20 early treatment discontinuations) or unknown reasons (n = 30). Of the 1067 patients in the EP, 97.4% achieved SVR. SVR rates in the EP were ≥95% when stratified by type of mental health disorder and other complicating baseline characteristics, including active injection drug use and antipsychotic drug use. Of 461 patients with data available in the EP, only 2% had an adherence level < 90% and 1% had an adherence level < 80%; all achieved SVR. Patients with mental health disorders can be cured of HCV using a well-tolerated, pangenotypic, protease inhibitor-free SOF/VEL regimen. This DAA allows the implementation of a simple treatment algorithm, with minimal monitoring requirements and fewer interactions with central nervous system drugs compared with protease-inhibitor DAA regimens.

Cost-effectiveness of remdesivir plus usual care versus usual care alone for hospitalized patients with COVID-19: an economic evaluation as part of the Canadian Treatments for COVID-19 (CATCO) randomized clinical trial.

BACKGROUND: The role of remdesivir in the treatment of hospitalized patients with COVID-19 remains ill-defined. We conducted a cost-effectiveness analysis alongside the Canadian Treatments for COVID-19 (CATCO) open-label, randomized clinical trial evaluating remdesivir. METHODS: Patients with COVID-19 in Canadian hospitals from Aug. 14, 2020, to Apr. 1, 2021, were randomly assigned to receive remdesivir plus usual care versus usual care alone. Taking a public health care payer's perspective, we collected in-hospital outcomes and health care resource utilization alongside estimated unit costs in 2020 Canadian dollars over a time horizon from randomization to hospital discharge or death. Data from 1281 adults admitted to 52 hospitals in 6 Canadian provinces were analyzed. RESULTS: The total mean cost per patient was $37 918 (standard deviation [SD] $42 413; 95% confidence interval [CI] $34 617 to $41 220) for patients randomly assigned to the remdesivir group and $38 026 (SD $46 021; 95% CI $34 480 to $41 573) for patients receiving usual care (incremental cost -$108 [95% CI -$4953 to $4737], p > 0.9). The difference in proportions of in-hospital deaths between remdesivir and usual care groups was -3.9% (18.7% v. 22.6%, 95% CI -8.3% to 1.0%, p = 0.09). The difference in proportions of incident invasive mechanical ventilation events between groups was -7.0% (8.0% v. 15.0%, 95% CI -10.6% to -3.4%, p = 0.006), whereas the difference in proportions of total mechanical ventilation events between groups was -5.7% (16.4% v. 22.1%, 95% CI -10.0% to -1.4%, p = 0.01). Remdesivir was the dominant intervention (but only marginally less costly, with mildly lower mortality) with an incalculable incremental cost effectiveness ratio; we report results of incremental costs and incremental effects separately. For willingness-to-pay thresholds of $0, $20 000, $50 000 and $100 000 per death averted, a strategy using remdesivir was cost-effective in 60%, 67%, 74% and 79% of simulations, respectively. The remdesivir costs were the fifth highest cost driver, offset by shorter lengths of stay and less mechanical ventilation. INTERPRETATION: From a health care payer perspective, treating patients hospitalized with COVID-19 with remdesivir and usual care appears to be preferrable to treating with usual care alone, albeit with marginal incremental cost and small clinical effects. The added cost of remdesivir was offset by shorter lengths of stay in the intensive care unit and less need for ventilation. STUDY REGISTRATION: ClinicalTrials. gov, no. NCT04330690.

Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial.

BACKGROUND: The role of remdesivir in the treatment of patients in hospital with COVID-19 remains ill defined in a global context. The World Health Organization Solidarity randomized controlled trial (RCT) evaluated remdesivir in patients across many countries, with Canada enrolling patients using an expanded data collection format in the Canadian Treatments for COVID-19 (CATCO) trial. We report on the Canadian findings, with additional demographics, characteristics and clinical outcomes, to explore the potential for differential effects across different health care systems. METHODS: We performed an open-label, pragmatic RCT in Canadian hospitals, in conjunction with the Solidarity trial. We randomized patients to 10 days of remdesivir (200 mg intravenously [IV] on day 0, followed by 100 mg IV daily), plus standard care, or standard care alone. The primary outcome was in-hospital mortality. Secondary outcomes included changes in clinical severity, oxygen- and ventilator-free days (at 28 d), incidence of new oxygen or mechanical ventilation use, duration of hospital stay, and adverse event rates. We performed a priori subgroup analyses according to duration of symptoms before enrolment, age, sex and severity of symptoms on presentation. RESULTS: Across 52 Canadian hospitals, we randomized 1282 patients between Aug. 14, 2020, and Apr. 1, 2021, to remdesivir (n = 634) or standard of care (n = 648). Of these, 15 withdrew consent or were still in hospital, for a total sample of 1267 patients. Among patients assigned to receive remdesivir, in-hospital mortality was 18.7%, compared with 22.6% in the standard-of-care arm (relative risk [RR] 0.83 (95% confidence interval [CI] 0.67 to 1.03), and 60-day mortality was 24.8% and 28.2%, respectively (95% CI 0.72 to 1.07). For patients not mechanically ventilated at baseline, the need for mechanical ventilation was 8.0% in those assigned remdesivir, and 15.0% in those receiving standard of care (RR 0.53, 95% CI 0.38 to 0.75). Mean oxygen-free and ventilator-free days at day 28 were 15.9 (± standard deviation [SD] 10.5) and 21.4 (± SD 11.3) in those receiving remdesivir and 14.2 (± SD 11) and 19.5 (± SD 12.3) in those receiving standard of care (p = 0.006 and 0.007, respectively). There was no difference in safety events of new dialysis, change in creatinine, or new hepatic dysfunction between the 2 groups. INTERPRETATION: Remdesivir, when compared with standard of care, has a modest but significant effect on outcomes important to patients and health systems, such as the need for mechanical ventilation. Trial registration: ClinicalTrials.gov, no. NCT04330690.

Real-life experience with ceftolozane/tazobactam in Canada: results from the CLEAR (Canadian LEadership on Antimicrobial Real-life usage) registry.

OBJECTIVES: Ceftolozane/tazobactam is a cephalosporin/ß-lactamase inhibitor combination with activity against Gram-negative bacilli. Here we report the use of ceftolozane/tazobactam in Canada using a national registry. METHODS: The CLEAR registry uses a REDCapTM online survey to capture details associated with clinical use of ceftolozane/tazobactam. RESULTS: Data from 51 patients treated in 2020 with ceftolozane/tazobactam are available. Infections treated included hospital-acquired bacterial pneumonia (37.3% of patients), ventilator-associated bacterial pneumonia (15.7%), bone and joint infection (11.8%), complicated intra-abdominal infection (7.8%) and complicated skin and skin-structure infection (7.8%). Moreover, 17.6% of patients had bacteraemia and 47.1% were in intensive care. Ceftolozane/tazobactam was primarily used as directed therapy for Pseudomonas aeruginosa infections (92.2% of patients). Ceftolozane/tazobactam was used because of resistance to (86.3%), failure of (11.8%) or adverse effects from (2.0%) previously prescribed antimicrobials. Ceftolozane/tazobactam susceptibility testing was performed on isolates from 88.2% of patients. Ceftolozane/tazobactam was used in combination with another antimicrobial active against Gram-negative bacilli in 39.2% of patients [aminoglycosides (15.7%), fluoroquinolones (9.8%) and colistin/polymyxin B (7.8%)]. The dosage regimen was customised in all patients based on creatinine clearance. The treatment duration was primarily >10 days (60.8% of patients), with microbiological success in 60.5% and clinical success in 64.4% of patients. Moreover, 7.8% of patients had adverse effects not requiring drug discontinuation. CONCLUSION: In Canada, ceftolozane/tazobactam is used as directed therapy to treat a variety of severe infections caused by multidrug-resistant P. aeruginosa. It is commonly used in combination with other antimicrobials with relatively high microbiological/clinical cure rates and an excellent safety profile.

Salvage Therapy with Sofosbuvir/Velpatasvir/Voxilaprevir in DAA-experienced Patients: Results from a Prospective Canadian Registry.

BACKGROUND: Despite the current highly effective therapies with direct-acting antiviral agents (DAAs), some patients with chronic hepatitis C virus (HCV) infection still do not achieve sustained virological response (SVR) and require retreatment. Sofosbuvir/velpatasvir/voxilaprevir (SVV) is recommended as the first-line retreatment option for most patients. The aim of this study was to evaluate the efficacy of SVV as salvage therapy after at least one course of DAA. METHODS: Data were collected on all HCV-infected patients who failed DAAs and were prescribed SVV from a prospective Canadian registry (CANUHC) including 17 sites across Canada. Factors associated with failure to achieve SVR with SVV therapy and the utility of RAS testing and ribavirin use were evaluated. RESULTS: A total of 128 patients received SVV after non-SVR with DAA treatment: 80% male, median age 57.5 (31-86), 44% cirrhotic, and 17 patients post liver transplant. First line regimens included: sofosbuvir/velpatasvir (27.3%), sofosbuvir/ledipasvir (26.5%), grazoprevir/elbasvir (12.5%), other (33.5%). Ribavirin was added to SVV in 26 patients due to past sofosbuvir/velpatasvir use (n = 8), complex resistance associated substitution profiles (n = 16) and/or cirrhosis (n = 9). Overall SVR rate was 96% (123/128). Of 35 patients who previously failed sofosbuvir/velpatasvir, 31 (88.5%) achieved SVR compared to 92 of 93 (99%) among those receiving any other regimen (P = .01). CONCLUSIONS: Similar to reports from phase 3 clinical trials, SVV proved highly effective as salvage therapy for patients who failed a previous DAA therapy. Those who failed SVV had at least 2 of the following factors: genotype 3, presence of cirrhosis, past liver transplantation, past exposure to sofosbuvir/velpatasvir and/or complex resistance profiles.

Standard versus combined chemical, mechanical, and heat decontamination of hospital drains harboring carbapenemase-producing organisms (CPOs): A randomized controlled trial.

We sought to determine whether combined chemical, mechanical, and heat cleaning was superior to standard cleaning for the decontamination of 32 sink and shower drains harboring carbapenemase-producing organisms (CPOs). Of 16 intervention drains, 10 (63%) were decontaminated until day 7 versus 1 (5%) of 16 comparator drains (P = .002). Intensive cleaning may be useful if administered repeatedly in drain-associated CPO outbreaks.

Hepatitis C direct-acting antiviral outcomes in patients 75 years and older.

BACKGROUND AND AIM: Elderly patients with hepatitis C virus (HCV) infection have worse interferon-based treatment outcomes than young patients. Direct-acting antiviral (DAA) regimens have enabled the treatment of previously difficult-to-cure populations. There are few studies that specifically assess DAA treatment outcomes in patients over 75 years of age. METHODS: Design: This was a cohort study. Setting: The setting was three Canadian HCV specialty sites. Participants: Patients aged 75 years and older and treated with DAA without interferon were enrolled. Measurements: Patient demographics, liver fibrosis by transient elastography, treatment regimen, and treatment outcome data were collected. RESULTS: The mean age of 78 patients in our analysis was 78.6 years (SD 3.5; range: 75-88 years). The most common genotype was 1b (35%). The most frequently utilized regimens included sofosbuvir-velpatasvir (33%) and ledipasvir-sofosbuvir (32%). Ribavirin was included for 17% of recipients. Sustained virological response (SVR) was achieved in 94% of patients (69% of those receiving ribavirin and 98% of patients on ribavirin-free regimens). Ribavirin toxicity contributed to the lower SVR rates in ribavirin-exposed patients. Ribavirin dosage was decreased in three patients and ultimately discontinued in two of these patients. All treatment was discontinued in another two patients. CONCLUSION: Ribavirin-free DAA therapy is safe and achieves SVR rates in older adults comparable to those described in the general population. RBV inclusion frequently results in complications, often leads to treatment modification or interruption, and does not improve SVR rates in those with advanced age.

Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial.

BACKGROUND: To date, only monoclonal antibodies have been shown to be effective for outpatients with COVID-19. Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. We aimed to investigate the safety and efficacy of peginterferon lambda in the treatment of outpatients with mild-to-moderate COVID-19. METHODS: In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of peginterferon lambda 180 µg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. Participants were randomly assigned (1:1) using a computer-generated randomisation list created with a randomisation schedule in blocks of four. At the time of administration, study nurses received a sealed opaque envelope with the treatment allocation number. The primary endpoint was the proportion of patients who were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on day 7 after the injection, analysed by a χ2 test following an intention-to-treat principle. Prespecified analysis of the primary endpoint, adjusted for baseline viral load, using bivariate logistic regression was done. The trial is now complete. This trial is registered with ClinicalTrials.gov, NCT04354259. FINDINGS: Between May 18, and Sept 4, 2020, we recruited 30 patients per group. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2·42 log copies per mL at day 7 (p=0·0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p=0·15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (odds ratio [OR] 4·12 [95% CI 1·15-16·73; p=0·029). Of those with baseline viral load above 106 copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6·25 [95% CI 1·49-31·06]; p=0·012). Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group. Two individuals met the threshold of grade 3 increase, one in each group, and no other grade 3 or 4 laboratory adverse events were reported. INTERPRETATION: Peginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding. FUNDING: The Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Real-life experience with ceftobiprole in Canada: Results from the CLEAR (CanadianLEadership onAntimicrobialReal-life usage) registry.

OBJECTIVES: Ceftobiprole is an advanced-generation cephalosporin with a favourable safety profile. Published data on the clinical use of ceftobiprole are limited. We report use of ceftobiprole in Canadian patients using data captured by the CLEAR registry. METHODS: The CLEAR registry uses the web-based research data management program REDCap™ (online survey) to facilitate clinicians entering details associated with their clinical experiences using ceftobiprole. RESULTS: Data were available for 38 patients treated with ceftobiprole. The most common infections treated were endocarditis (42.1% of patients), bone and joint infection (23.7%) and hospital-associated bacterial pneumonia (15.8%). 92.1% of patients had bacteraemia and 21.1% were in intensive care. Ceftobiprole was used because of failure of (71.1%), resistance to (18.4%) or adverse effects from (10.5%) previously prescribed antimicrobial agents. Ceftobiprole was primarily used as directed therapy for methicillin-resistant Staphylococcus aureus (MRSA) infections (94.7% of patients). Ceftobiprole susceptibility testing was performed on isolates from 47.4% of patients. It was used concomitantly with daptomycin in 55.3% of patients and with vancomycin in 18.4% of patients. Treatment duration was primarily >10 days (65.8% of patients) with microbiological success in 97.0% and clinical success in 84.8% of patients. 2.6% of patients had gastrointestinal adverse effects. CONCLUSION: In Canada to date, ceftobiprole is used as directed therapy to treat a variety of severe infections caused by MRSA. It is primarily used in patients failing previous antimicrobials, is frequently added to, and thus used in combination with daptomycin or vancomycin with high microbiological and clinical cure rates and an excellent safety profile.

Squamous Cell Proliferation as a Reactive Mechanism to Laryngeal Cryptococcus Infection: A Case Report.

Cryptococcus neoformans (C. neoformans) is a ubiquitous encapsulated, obligate anaerobe, a dimorphic fungus that can be pathogenic in humans. C. neoformans infections arise primarily in immunocompromised individuals, such as human immunodeficiency virus (HIV) patients, as well as those who use inhaled corticosteroids regularly. Due to the wide variety of clinical findings associated with C. neoformans, infection within the head and neck is occasionally misdiagnosed as malignancy due to its protean manifestation. In this report, we describe the case of a C. neoformans infection resulting in an initial misdiagnosis due to an overlying laryngeal squamous cell proliferation mimicking laryngeal squamous cell carcinoma (SCC). This case is intended to provide further evidence for inhaled corticosteroid use predisposing patients to fungal infections, as well as to provide insight into the possible mechanism resulting in the initial diagnosis of malignancy. A review of recent literature is also discussed.

Direct-acting antiviral treatment uptake and sustained virological response outcomes are not affected by alcohol use: A CANUHC analysis.

Background: Alcohol use and hepatitis C virus (HCV) are two leading causes of liver disease. Alcohol use is prevalent among the HCV-infected population and accelerates the progression of HCV-related liver disease. Despite barriers to care faced by HCV-infected patients who use alcohol, few studies have analyzed uptake of direct-acting antiviral (DAA) treatment. Objective: We compared rates of treatment uptake and sustained virological response (SVR) between patients with and without alcohol use. Methods: Prospective data were obtained from the Canadian Network Undertaking against Hepatitis C (CANUHC) cohort. Consenting patients assessed for DAA treatment between January 2016 and December 2019 were included. Demographic and clinical characteristics were compared between patients with and without alcohol use by means of t-tests, χ2 tests, and Fisher's Exact Tests. Univariate and multivariate analyses were used to determine predictors of SVR and treatment initiation. Results: Current alcohol use was reported for 217 of 725 (30%) patients. The proportion of patients initiating DAA treatment did not vary by alcohol use status (82% versus 83%; p = 0.99). SVR rate was similar between patients with alcohol use and patients without alcohol use (92% versus 94%; p = 0.45). Univariate and multivariate analysis found no association between alcohol use and SVR or treatment initiation. Conclusion: Patients engaged in HCV treatment have highly favourable treatment uptake and outcomes regardless of alcohol use. Public health interventions should be directed toward facilitating access to care for all patients irrespective of alcohol use. Research into high-level alcohol use and DAA outcomes is needed.

Hepatitis C virus infection characteristics and treatment outcomes in Canadian immigrants.

BACKGROUND: There are multiple obstacles encountered by immigrants attempting to engage hepatitis C virus (HCV) care and treatment. We evaluated the diversity and treatment outcomes of HCV-infected immigrants evaluated for Direct Acting Antiviral (DAA) therapy in Canada. METHODS: The Canadian Network Undertaking against Hepatitis C (CANUHC) Cohort contains demographic information and DAA treatment information prospectively collected at 10 Canadian sites. Information on country of origin and race are collected. Characteristics and outcomes (sustained virological response; SVR) were compared by immigration status and race. RESULTS: Between January 2016 and May 2018, 725 HCV-infected patients assessed for DAA therapy were enrolled in CANUHC (mean age: 52.66 ± 12.68 years); 65.66% male; 82.08% White, 5.28% Indigenous, 4.64% South East Asian, 4.64% East Indian, 3.36% Black). 18.48% were born outside of Canada. Mean age was similar [immigrants: 54.36 ± 13.95 years), Canadian-born: 52.27 ± 12.35 years); (p = 0.085)]. The overall baseline fibrosis score (in kPa measured by transient elastography) was similar among Canadian and foreign-born patients. Fibrosis score was not predicted by race or genotype. The proportion initiating DAA therapy was similar by immigrant status (56.72% vs 49.92%). SVR rates by intent-to-treat analysis were similar (immigrants-89.47%, Canadian-born-92.52%; p = 0.575). CONCLUSION: A diverse immigrant population is engaging care in Canada, initiating HCV antiviral therapy in an equitable fashion and achieving SVR proportions similar to Canada-born patients. Our Canadian experience may be of value in informing HCV elimination efforts in economically developed regions.

Global real-world evidence of sofosbuvir/velpatasvir as simple, effective HCV treatment: Analysis of 5552 patients from 12 cohorts.

BACKGROUND AND AIMS: Achieving sustained virological response (SVR; cure) in hepatitis C patients using a simple regimen is key to making elimination by 2030 possible. In the largest real-world analysis to date, the effectiveness of pangenotypic, panfibrotic, single-tablet, sofosbuvir/velpatasvir (SOF/VEL) once-daily for 12 weeks was assessed in 12 clinical real-world cohorts from various geographical areas, settings and treatment practices. Factors affecting risk of not achieving SVR were assessed. METHODS: Adults treated with SOF/VEL 400/100 mg, without ribavirin, were included. All HCV patients reaching Week 12 or 24 post-treatment were assessed for SVR12/24. Factors associated with not achieving SVR12/24 for virological reasons were evaluated using logistic regression analysis. RESULTS: Overall, 5552 patients were included: 13.3% treatment-experienced; 20.7% compensated cirrhotic; 30.2% genotype 1; 29.5% genotype 2; 32.9% genotype 3; 4.7% genotype 4; 3.7% HIV coinfection; 13.4% current/former intravenous drug use. Of the 5196 patients evaluated for effectiveness, 98.9% achieved SVR12/24. High SVR12/24 rates occurred in all genotypes including genotype 3 (98.3%; 1649/1677) and in those with compensated cirrhosis (97.9; 1055/1078). Only 55 patients did not achieve SVR12/24 due to a virological reason; the only factor statistically significantly associated with an increased risk of not achieving SVR12/24 was compensated cirrhosis (P = .002). Overall, 6% (332/5552) of patients did not achieve SVR12/24 for non-virological reasons (67% lost to follow-up; 26.5% early treatment discontinuation). CONCLUSIONS: In this large cohort, representative of clinical practice, a simple 12-week regimen of SOF/VEL without ribavirin resulted in high SVR12/24 rates in diverse patient populations, even among those with compensated cirrhosis.

The Z-Profile Study: a multicenter, retrospective cohort study to assess the real-world use and effectiveness of elbasvir/grazoprevir in Canadian adult patients with chronic hepatitis C.

Background: Canada was the first country to approve elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic HCV infection for genotypes 1 and 4 with or without ribavirin and genotype 3 with sofosbuvir, with no recommendation for baseline resistance testing. The aim of this study was to describe the effectiveness of EBR/GZR and the profile of patients selected for treatment in a Canadian real-world setting. Methods: This multicenter retrospective study of HCV-infected patients treated with EBR/GZR took place among selected Canadian health care providers, with no exclusion criteria. Primary outcome measures included parameters associated with patient profile and sustained virologic response at 12 weeks (SVR12) and 24 weeks after treatment. Results: A total of 408 patients were included; 244 had available SVR12 information (per-protocol population [PP]). Genotype distribution included 1a (54.7%), 1b (17.2%), 3 (11.8%), 4 (10.0%), and other (6.4%). The majority (88.7%) of participants were treated for 12 weeks without ribavirin. Fifty-nine (14.5%) participants, predominantly with genotype 1a (49/59) infection, were tested for baseline resistance-associated substitutions (bRAS). SVR12 was achieved by 95.9% of the PP. In an exploratory analysis assessing potential predictors of SVR12, participants who had undergone bRAS testing (OR 0.14, 95% CI 0.03-0.64) and participants who had undergone liver transplant (OR 0.05, 95% CI 0.00-0.68) had significantly lower odds of achieving SVR12. Conclusions: This study supports the real-world effectiveness of EBR/GZR-including a broad range of genotypes and diverse fibrosis stages-in the absence of bRAS testing and in special populations.

Infection prevention and control practices related to carbapenemase-producing Enterobacteriaceae (CPE) in acute-care hospitals in Ontario, Canada.

OBJECTIVE: To determine infection prevention and control (IPAC) practices for carbapenemase-producing Enterobacteriaceae (CPE), an emerging threat, at acute-care hospitals in Ontario, Canada. DESIGN: A descriptive cross-sectional survey. METHODS: We surveyed IPAC directors and managers at all acute-care hospitals in Ontario, Canada, to gather information on IPAC practices related to CPE, including admission screening, other patient screening, environmental testing, use of precautions to prevent transmission, and outbreak management. RESULTS: Of 116 acute-care hospitals, 105 (91%) responded. Admission screening included patients previously colonized or infected with CPE (n = 64, 61%), patients recently hospitalized outside of Canada (Indian subcontinent, n = 62, 59%; other countries, n = 56, 53%), and patients recently hospitalized in Canada (n = 22, 21%). Fifty-one hospitals (49%) screened patients for colonization during an outbreak. Almost all hospitals (n = 101, 96%) used precautions to prevent transmission from patients with CPE colonization or infection; most hospitals (n = 54, 53%) continued precautions indefinitely. Few hospitals (n = 19, 18%) performed environmental cultures. Eight hospitals (8%) reported at least 1 outbreak, and 6 hospitals (6%) reported transmission from sink or shower drains to patients. CONCLUSIONS: Variability in practices may result from lack of evidence and challenges in updating guidelines as evidence emerges. A coordinated approach to slow the emergence of CPE should be considered in our population.

Sofosbuvir/velpatasvir for 12 weeks in hepatitis C virus-infected patients with end-stage renal disease undergoing dialysis.

BACKGROUND & AIMS: Although off-label use of sofosbuvir-containing regimens occurs regularly in patients with hepatitis C virus (HCV) infection undergoing dialysis for severe renal impairment or end-stage renal disease (ESRD), these regimens are not licensed for this indication, and there is an absence of dosing recommendations in this population. This study evaluated the safety and efficacy of sofosbuvir/velpatasvir in patients with HCV infection with ESRD undergoing dialysis. METHODS: In this phase II, single-arm study, 59 patients with genotype 1-6 HCV infection with ESRD undergoing hemodialysis or peritoneal dialysis received open-label sofosbuvir/velpatasvir (400 mg/100 mg) once daily for 12 weeks. Patients were HCV treatment naive or treatment experienced without cirrhosis or with compensated cirrhosis. Patients previously treated with any HCV NS5A inhibitor were not eligible. The primary efficacy endpoint was the proportion of patients achieving sustained virologic response (SVR) 12 weeks after discontinuation of treatment (SVR12). The primary safety endpoint was the proportion of patients who discontinued study drug due to adverse events. RESULTS: Overall, 56 of 59 patients achieved SVR12 (95%; 95% CI 86-99%). Of the 3 patients who did not achieve SVR12, 2 patients had virologic relapse determined at post-treatment Week 4 (including 1 who prematurely discontinued study treatment), and 1 patient died from suicide after achieving SVR through post-treatment Week 4. The most common adverse events were headache (17%), fatigue (14%), nausea (14%), and vomiting (14%). Serious adverse events were reported for 11 patients (19%), and all were deemed to be unrelated to sofosbuvir/velpatasvir. CONCLUSIONS: Treatment with sofosbuvir/velpatasvir for 12 weeks was safe and effective in patients with ESRD undergoing dialysis. LAY SUMMARY: Sofosbuvir/velpatasvir is a combination direct-acting antiviral that is approved for treatment of patients with hepatitis C virus (HCV) infection. Despite the lack of dosing recommendations, sofosbuvir-containing regimens (including sofosbuvir/velpatasvir) are frequently used for HCV-infected patients undergoing dialysis. This study evaluated the safety and efficacy of sofosbuvir/velpatasvir for 12 weeks in patients with HCV infection who were undergoing dialysis. Treatment with sofosbuvir/velpatasvir was safe and well tolerated, resulting in a cure rate of 95% in patients with HCV infection and end-stage renal disease. Clinical Trial Number: NCT03036852.

Identification of 19 Novel Hepatitis C Virus Subtypes-Further Expanding HCV Classification.

BACKGROUND: Hepatitis C virus (HCV) is currently classified into 8 genotypes and 86 subtypes. The objective of this study was to characterize novel HCV subtypes and to investigate the impact of subtypes on treatment outcome. METHODS: Full-genome sequencing was performed on HCV plasma samples with <85% sequence homology of NS3, NS5A, and/or NS5B to HCV genotype (GT) 1-8 reference strains. RESULTS: A total of 14 653 patients with GT1-6 HCV infection were enrolled in clinical studies of sofosbuvir-based regimens. For the majority of the patients, a specific subtype could be assigned based on a close genetic relationship to previously described subtypes. However, for 19 patients, novel subtypes were identified with <85% homology compared with previously described subtypes. These novel subtypes had the following genotypes: 9 in GT2, 5 in GT4, 2 in GT6, and 1 each in GT1, GT3, and GT5. Despite the presence of polymorphisms at resistance-associated substitution positions, 18 of the 19 patients treated with sofosbuvir-containing therapy achieved SVR12. CONCLUSIONS: Nineteen novel HCV subtypes were identified, suggesting an even greater genetic diversity of HCV subtypes than previously recognized.

Real-world health care utilization in treatment of HCV: Results from the Canadian SIMPLE observational trial.

Background: As hepatitis C virus (HCV) treatment continues to evolve, there is an ongoing need to understand and optimize real-world disease management. The primary objective of the SIMPLE study was to describe the real-life management of genotype 1 (G1) HCV in Canada treated with boceprevir + pegylated interferon and ribavirin therapy. Methods: This was an observational, prospective cohort, multicentre, non-interventional study of patients with G1 HCV. A single cohort of adult patients were to be managed as per standard of care (SoC) and treated with 4 weeks of PegRBV dual therapy, followed by boceprevir + PegRBV for 24-44 weeks, with 24-weeks follow-up. Treatment compliance, health care resource utilization (HCRU), HCV viral load, and hematological adverse event (AE) data were collected. Results: This study enrolled 159 patients. All investigators were well educated on the Canadian consensus guidelines for HCV management but only a minority of patients were treated according to treatment guidelines. Viral response was achieved by >50% of patients by week 8 of therapy and in 50%-60% of tested patients during follow-up. An average of 17.9 HCRU visits were reported during the study period. The most commonly used resources were nursing visits for routine follow-up. Conclusions: Results from this real-world study suggest that most patients were not treated according to the product monograph. Further studies are required to determine how oral treatments fit into this paradigm and how these findings extrapolate to the current treatment model. This study can serve as a benchmark for future real-world treatment including heath care utilization analyses.