Hepatitis C virus-specific immune responses following direct-acting antivirals administered during recent hepatitis C virus infection.

Individuals who spontaneously clear hepatitis C virus (HCV) infection have demonstrated evidence of partial protective immunity, whereas treatment-induced clearance provides little or no protection against reinfection. We aimed to investigate whether treatment of acute HCV infection with direct-acting antivirals (DAA) prevents establishment of, or reverses, T-cell exhaustion, leading to a virus-specific T-cell immune profile more similar to that seen in spontaneous clearance. The magnitude and breadth of HCV-specific T-cell responses before and after DAA or interferon-based therapy in acute or chronic HCV were compared to those of participants with spontaneous clearance of infection, using Enzyme-linked Immunospot (ELISPOT). PBMCs were available for 55 patients comprising 4 groups: spontaneous clearance (n = 17), acute interferon (n = 14), acute DAA (n = 13) and chronic DAA (n = 11). After controlling for sex, the magnitude of post-treatment HCV-specific responses after acute DAA treatment was greater than after chronic DAA or acute IFN treatment and similar to those found in spontaneous clearers. However, spontaneous clearers responded to more HCV peptide pools indicating greater breadth of response. In conclusion, early treatment with DAAs may prevent or reverse some degree of immune exhaustion and result in stronger HCV-specific responses post-treatment. However, individuals with spontaneous clearance had broader HCV-specific responses.

Effectiveness of scheduled vital signs assessment during infliximab infusions in detecting infusion reactions: a multi-centre retrospective data review.

PURPOSE: To determine if scheduled vital signs monitoring is useful in the detection of infusion reactions to infliximab (IFX). METHODS: The infusion records of 35,988 IFX infusions completed in 2017 were reviewed for infusion reactions that occurred during the infusion, which were then examined further to determine how those infusion reactions were detected. RESULTS: Of the 90 complete infusion reaction records reviewed, no infusion reactions (0) were detected by scheduled vital signs assessment. CONCLUSIONS: According to the infusion reaction data reviewed, scheduled vital sign assessment did not detect any infusion reactions and may not be necessary for the purpose of monitoring patients during infusions for early detection of infusion reactions. Previous research into IFX infusion reactions reviewed also concluded that scheduled vital signs assessment may not be helpful in the detection of infusion reactions and, in many cases, vital signs did not vary significantly enough from baseline to signal an infusion reaction.

Evaluation of Dried Blood Spot Testing for SARS-CoV-2 Serology Using a Quantitative Commercial Assay.

Dried blood spots (DBS) are commonly used for serologic testing for viruses and provide an alternative collection method when phlebotomy and/or conventional laboratory testing are not readily available. DBS collection could be used to facilitate widespread testing for SARS-CoV-2 antibodies to document past infection, vaccination, and potentially immunity. We investigated the characteristics of Roche's Anti-SARS-CoV-2 (S) assay, a quantitative commercial assay for antibodies against the spike glycoprotein. Antibody levels were reduced relative to plasma following elution from DBS. Quantitative results from DBS samples were highly correlated with values from plasma (r2 = 0.98), allowing for extrapolation using DBS results to accurately estimate plasma antibody levels. High concordance between plasma and fingerpick DBS was observed in PCR-confirmed COVID-19 patients tested 90 days or more after the diagnosis (45/46 matched; 1/46 mismatched plasma vs. DBS). The assessment of antibody responses to SARS-CoV-2 using DBS may be feasible using a quantitative anti-S assay, although false negatives may rarely occur in those with very low antibody levels.

Cognitive Dysfunction, Brain Volumes, and Traumatic Brain Injury in Homeless Persons.

Although homeless persons experience traumatic brain injury (TBI) frequently, little is known about the structural and functional brain changes in this group. We aimed to describe brain volume changes and related cognitive/motor deficits in homeless persons with or without TBI versus controls. Participants underwent T1-weighted magnetic resonance imaging (MRI), neuropsychological (NP) tests (the Grooved Pegboard Test [GPT]/Finger Tapping Test [FTT]), alcohol/drug use screens (the Alcohol Use Disorders Identification Test [AUDIT]/Drug Abuse Screening Test [DAST]), and questionnaires (the Brain Injury Screening Questionnaire [BISQ]/General Information Questionnaire [GIQ]) to determine TBI. Normalized volumes of brain substructures from MRI were derived from FreeSurfer. Comparisons were tested by Mann-Whitney U and Kruskal-Wallis rank sum tests. Leave-one-out cross-validation using random forest classifier was applied to determine the ability of predicting TBI. Diagnostic ability of this classifier was assessed using area under the receiver operating characteristic curve (AUC). Fifty-one participants-25 homeless persons (9 with TBI) and 26 controls-were included. The homeless group had higher AUDIT scores and smaller thalamus and brainstem volumes (p < 0.001) than controls. Within homeless participants, the TBI group had reduced normalized volumes of nucleus accumbens, thalamus, ventral diencephalon, and brainstem compared with the non-TBI group (p < 0.001). Homeless participants took more time on the GPT compared with controls using both hands (p < 0.0001); but the observed effects were more pronounced in the homeless group with TBI in the non-dominant hand. Homeless persons with TBI had fewer dominant hand finger taps than controls (p = 0.0096), and homeless participants with (p = 0.0148) or without TBI (p = 0.0093) tapped less than controls with their non-dominant hand. In all participants, TBI was predicted with an AUC of 0.95 (95% confidence interval [CI]: 0.89-1.00) by the classifier modeled on MRI, NP tests, and screening data combined. The MRI-data-based classifier was the best predictor of TBI within the homeless group (AUC: 0.76, 95% CI: 0.53-0.99). Normalized volumes of specific brain substructures were important indicators of TBI in homeless participants and they are important indicators of TBI in the state of homelessness itself. They may improve predictive ability of NP and screening tests in determining these outcomes.

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.

The 9th Canadian Symposium on Hepatitis C Virus: Advances in HCV research and treatment towards elimination.

Hepatitis C virus (HCV) elimination has evolved into a coordinated global effort. Canada, with more than 250,000 chronically infected individuals, is among the countries leading this effort. The 9th Canadian Symposium on HCV, held in February 2020, thus established and addressed its theme, 'advances in HCV research and treatment towards elimination', by gathering together basic scientists, clinicians, epidemiologists, social scientists, and community members interested in HCV research in Canada. Plenary sessions showcased topical research from prominent international and national researchers, complemented by select abstract presentations. This event was hosted by the Canadian Network on Hepatitis C (CanHepC), with support from the Public Health Agency of Canada and the Canadian Institutes of Health Research and in partnership with the Canadian Liver Meeting. CanHepC has an established record in HCV research by its members and in its advocacy activities to address the care, treatment, diagnosis, and immediate and long-term needs of those affected by HCV infection. Many challenges remain in tackling chronic HCV infection, such as the need for a vaccine; difficult-to-treat populations and unknown aspects of patient subgroups, including pregnant women and children; vulnerable people; and issues distinct to Indigenous peoples. There is also increasing concern about long-term clinical outcomes after successful treatment, with the rise in comorbidities such as diabetes, cardiovascular disease, and fatty liver disease and the remaining risk for hepatocellular carcinoma in cirrhotic individuals. The symposium addressed these topics in highlighting research advances that will collectively play an important role in eliminating HCV and minimizing subsequent health challenges.

Spontaneous Clearance After Relapse Following Direct-Acting Antiviral Treatment for Chronic HCV Infection.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) cure most cases of chronic hepatitis C virus (HCV) infection. However, a small percentage of patients relapse with reappearance of viremia after a full course of therapy. Although most who relapse require retreatment, some patients spontaneously clear HCV without additional therapy. We studied patients who relapsed with detectable HCV RNA after a full course of DAA therapy and then spontaneously cleared the HCV infection without retreatment. METHODS: We performed a case-control study of patients who spontaneously cleared chronic HCV infection following a documented relapse after DAA therapy at the Toronto Centre for Liver Disease, from January 2014 through December 2017. We collected clinical information at baseline, 12 weeks after treatment, and 6 months after relapse and compared data among spontaneous clearers, patients with persistent relapse, and patients who achieved a sustained virologic response to therapy 12 weeks after treatment (SVR12). The strength and breadth of interferon gamma cytokine secretion by HCV-specific T cells from peripheral blood were quantified using the ELISPOT assay. RESULTS: Of the 1032 individuals with chronic HCV infection who were treated with DAAs, 93 patients had a documented relapse. Of these patients, 12 patients (13%) spontaneously cleared HCV within 6 months after the documented relapse without additional therapy. The spontaneous clearers had low levels of HCV RNA (<4 log IU/mL in 11 of 12) and normal levels of alanine aminotransferase at the time of relapse, much like patients with an SVR12. There was no significant difference between the spontaneous clearance group and the SVR12 group in magnitude and breadth of HCV-specific T cell responses. CONCLUSIONS: In a case-control study of patients who spontaneously cleared chronic HCV infection following a relapse after DAA therapy, we found that it is important to confirm viremia prior to retreatment after the relapse-particularly for individuals with low levels of HCV RNA and normal or near-normal levels of alanine aminotransferase after treatment.

Reducing Read Time of Point-of-Care Test Does Not Affect Detection of Hepatitis C Virus and Reduces Need for Reflex RNA.

BACKGROUND & AIMS: Global elimination of hepatitis C virus (HCV) will require increases in diagnosis. Point of care (POC) tests that detect antibodies against HCV can be useful for testing large and difficult to reach populations. The most accurate POC test requires a 20 min read time to identify antibody-positive samples. We investigated whether viremic patients could be identified using a shorter read time, to increase efficiency and reduce the need for reflex tests (a follow-up test for HCV RNA on the same specimen to confirm viremia). METHODS: Patients with past or current HCV infections provided samples at 2 clinics in Canada for evaluation by the OraQuick HCV Rapid antibody POC test. A community HCV-screening program in Madrid, Spain (real-world cohort) invited people to be tested for HCV with the same OraQuick test. Patients provided samples of whole blood, via finger prick. Fingerprick samples were tested immediately after collection. In the clinic cohort, photographs of the developing test were taken at 15 second intervals, and blinded readers recorded the time to positivity. In the real-world cohort, readers recorded the OraQuick result at 5 minutes, and each minute after, up to 10 minutes, and then again at 20 minutes; viremia was then evaluated using a POC HCV RNA test (GeneXpert HCV Viral Load Assay). Sera from viremic and non-viremic clinic patients were used to quantify antibody titers to investigate the relationship between the time of band appearance and antibody concentration. Fisher's exact test and exact logistic regression were used to determine factors associated with a positive result at 5 minutes. RESULTS: Blood from all viremic patients produced a positive result in the antibody POC test by 5 min. Median time to a positive result for 171 viremic patients was 2.6 min (range, 1.8-4.6 min), vs 4.1 min (range, 2.3-14.4 min) for 108 patients with resolved infection (P < .001). The 5-min threshold identified all viremic cases among 176 HCV antibody-positive patients in the real-world cohort, confirmed by testing for HCV RNA. In the pooled cohorts, antibody positivity at 5 min identified viremic patients with 100% sensitivity (95% CI, 98.4%-100%); the negative predictive value was 100% (95% CI, 94.9%-100%). The positive predictive value at 5 min was 62.0% (95% CI, 56.7%-67.0%) and therefore insufficient alone to detect viremia; an HCV RNA test would still be necessary to confirm active infection. CONCLUSIONS: The wait time for the OraQuick HCV Rapid antibody POC blood test can be reduced from 20 min to 5 min and continue to reliably identify patients with HCV infection. Shortening the test time could increase high-throughput screening, reduce loss to follow up, and reduce the need for reflex HCV RNA testing.

Medical assessment of potential concussion in elite football: video analysis of the 2016 UEFA European championship.

OBJECTIVE: The objective is to determine if suspected concussions in elite football are medically assessed according to the International Conferences on Concussion in Sport consensus statement recommendations. SETTING: Men's Union of European Football Association (UEFA) Football Championship. PARTICIPANTS: All professional football players in the UEFA 2016 Championship Tournament. DESIGN: Observational study. OUTCOME MEASURES: Potential concussive events (PCEs) were defined as direct head collision incidents resulting in the athlete being unable to immediately resume play following impact. PCEs identified and description of PCE assessment and outcome were accomplished through direct standardised observation of video footage by trained observers in 51 games played in the Men's UEFA European Championship (10 June-10 July 2016). RESULTS: Sixty-nine total PCEs (1.35 per match) were identified in 51 games played during the 2016 Men's UEFA European Championship. Forty-eight PCEs (69.6%) resulted in two observable signs of concussion, 13 (18.8%) resulted in three signs and 1 (1.4%) resulted in four signs in the injured athletes. Nineteen (27.5%) PCEs were medically assessed by sideline healthcare personnel while 50 (72.5%) were not. Of the 50 PCEs that were not medically assessed, 44 (88%) PCEs resulted in two or more signs of concussion among injured athletes. Of the 19 medically assessed PCEs, 8 resulted in 3 signs of concussion, and 1 resulted in 4 signs; all assessments concluded in the same-game return for the injured athletes. CONCLUSIONS: PCEs were frequent events in the 2016 UEFA Euro championship, but were rarely assessed concordant with the International Conferences on Concussion in Sport consensus statement recommendations. There is an imperative need to improve the assessment and management of players suspected of concussion in elite football.

Restoration of HCV-Specific Immune Responses with Antiviral Therapy: A Case for DAA Treatment in Acute HCV Infection.

Worldwide, 71 million individuals are chronically infected with Hepatitis C Virus (HCV). Chronic HCV infection can lead to potentially fatal outcomes including liver cirrhosis and hepatocellular carcinoma. HCV-specific immune responses play a major role in viral control and may explain why approximately 20% of infections are spontaneously cleared before the establishment of chronicity. Chronic infection, associated with prolonged antigen exposure, leads to immune exhaustion of HCV-specific T cells. These exhausted T cells are unable to control the viral infection. Before the introduction of direct acting antivirals (DAAs), interferon (IFN)-based therapies demonstrated successful clearance of viral infection in approximately 50% of treated patients. New effective and well-tolerated DAAs lead to a sustained virological response (SVR) in more than 95% of patients regardless of viral genotype. Researchers have investigated whether treatment, and the subsequent elimination of HCV antigen, can reverse this HCV-induced exhausted phenotype. Here we review literature exploring the restoration of HCV-specific immune responses following antiviral therapy, both IFN and DAA-based regimens. IFN treatment during acute HCV infection results in greater immune restoration than IFN treatment of chronically infected patients. Immune restoration data following DAA treatment in chronically HCV infected patients shows varied results but suggests that DAA treatment may lead to partial restoration that could be improved with earlier administration. Future research should investigate immune restoration following DAA therapies administered during acute HCV infection.