COVID-19 vaccine immunogenicity in people with HIV.

OBJECTIVES: Many vaccines require higher/additional doses or adjuvants to provide adequate protection for people with HIV (PWH). Our objective was to compare COVID-19 vaccine immunogenicity in PWH to HIV-negative individuals. DESIGN: In a Canadian multi-center prospective, observational cohort of PWH receiving at least two COVID-19 vaccinations, we measured vaccine-induced immunity at 3 and 6 months post 2nd and 1-month post 3rd doses. METHODS: The primary outcome was the percentage of PWH mounting vaccine-induced immunity [co-positivity for anti-IgG against SARS-CoV2 Spike(S) and receptor-binding domain proteins] 6 months post 2nd dose. Univariable and multivariable logistic regressions were used to compare COVID-19-specific immune responses between groups and within subgroups. RESULTS: Data from 294 PWH and 267 controls were analyzed. Immunogenicity was achieved in over 90% at each time point in both groups. The proportions of participants achieving comparable anti-receptor-binding domain levels were similar between the group at each time point. Anti-S IgG levels were similar by group at month 3 post 2nd dose and 1-month post 3rd dose. A lower proportion of PWH vs. controls maintained vaccine-induced anti-S IgG immunity 6 months post 2nd dose [92% vs. 99%; odds ratio: 0.14 (95% confidence interval: 0.03, 0.80; P = 0.027)]. In multivariable analyses, neither age, immune non-response, multimorbidity, sex, vaccine type, or timing between doses were associated with reduced IgG response. CONCLUSION: Vaccine-induced IgG was elicited in the vast majority of PWH and was overall similar between groups. A slightly lower proportion of PWH vs. controls maintained vaccine-induced anti-S IgG immunity 6 months post 2nd dose demonstrating the importance of timely boosting in this population.

'I did not have sex outside of our bubble': changes in sexual practices and risk reduction strategies among sexual minority men in Canada during the COVID-19 pandemic.

In efforts to prevent the spread of COVID-19, jurisdictions across the globe, including Canada, enacted containment measures that affected intimacy and sexual relations. This article examines how public health measures during COVID-19 impacted the sexual practices of sexual minority men- gay, bisexual, queer and other men who have sex with men-and how they adopted and modified guidelines to prevent the transmission of COVID-19, HIV and other sexually transmitted infections (STIs). We conducted 93 semi-structured interviews with men (n = 93) in Montreal, Toronto and Vancouver, Canada, between November 2020 to February 2021 (n = 42) and June to October 2021 (n = 51). Across jurisdictions, participants reported changes to sexual practices in response to public health measures and shifting pandemic contexts. Many men indicated that they applied their HIV/STI risk mitigation experiences and adapted COVID-19 prevention strategies to continue engaging in casual sexual behaviours and ensure sexual safety. 'Social bubbles' were changed to 'sex bubbles'. Masks were turned into 'safer' sex tools. 'Outdoor gathering' and 'physical distancing' were transformed into 'outdoor sex' and 'voyeuristic masturbation'. These strategies are examined in connection to the notion of 'reflexive mediation' to illustrate how sexual minority men are simultaneously self-responsibilising and resistant, self-monitoring and creative.

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.

Increases in human papillomavirus vaccine coverage over 12 months among a community-recruited cohort of gay, bisexual, and other men who have sex with men in Canada.

BACKGROUND: Starting in 2015/16, most Canadian provinces introduced publicly-funded human papillomavirus (HPV) vaccination programs for gay, bisexual, and other men who have sex with men (GBM) aged ≤ 26 years. We estimated 12-month changes in HPV vaccine coverage among community-recruited GBM from 2017 to 2021 and identified baseline factors associated with vaccine initiation (≥1 dose) or series completion (3 doses) among participants who were unvaccinated or partially vaccinated at baseline. METHODS: We recruited sexually-active GBM aged ≥ 16 years in Montreal, Toronto, and Vancouver, Canada, from 02/2017 to 08/2019 and followed them over a median of 12 months (interquartile range = 12-13 months). We calculated the proportion who initiated vaccination (≥1 dose) or completed the series (3 doses) by 12-month follow-up. Analyses were stratified by city and age-eligibility for the publicly-funded programs at baseline (≤26 years or > 26 years). We used multivariable logistic regression to identify baseline factors associated with self-reported incident vaccine initiation or series completion. RESULTS: Among 165 unvaccinated participants aged ≤ 26 years at baseline, incident vaccine initiation (≥1 dose) during follow-up was 24.1% in Montreal, 33.3% in Toronto, and 38.9% in Vancouver. Among 1,059 unvaccinated participants aged > 26 years, incident vaccine initiation was 3.4%, 8.9%, and 10.9%, respectively. Higher education and trying to access pre-exposure prophylaxis for HIV were associated with incident vaccination among those aged ≤ 26 years, while younger age, residing in Vancouver (vs. Montreal), being diagnosed with anogenital warts, having both government and private extended medical insurance, and being vaccinated against influenza were associated with incident vaccination among those aged > 26 years. CONCLUSIONS: We observed substantial gains in HPV vaccine coverage among young GBM within 5 + years of targeted program implementation, but gaps remain, particularly among older men who are ineligible for publicly-funded programs. Findings suggest the need for expanded public funding or insurance coverage for HPV vaccines.

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.

Post-exposure prophylaxis against SARS-CoV-2 in close contacts of confirmed COVID-19 cases (CORIPREV): study protocol for a cluster-randomized trial.

BACKGROUND: Post-exposure prophylaxis (PEP) is a well-established strategy for the prevention of infectious diseases, in which recently exposed people take a short course of medication to prevent infection. The primary objective of the COVID-19 Ring-based Prevention Trial with lopinavir/ritonavir (CORIPREV-LR) is to evaluate the efficacy of a 14-day course of oral lopinavir/ritonavir as PEP against COVID-19 among individuals with a high-risk exposure to a confirmed case. METHODS: This is an open-label, multicenter, 1:1 cluster-randomized trial of LPV/r 800/200 mg twice daily for 14 days (intervention arm) versus no intervention (control arm), using an adaptive approach to sample size calculation. Participants will be individuals aged > 6 months with a high-risk exposure to a confirmed COVID-19 case within the past 7 days. A combination of remote and in-person study visits at days 1, 7, 14, 35, and 90 includes comprehensive epidemiological, clinical, microbiologic, and serologic sampling. The primary outcome is microbiologically confirmed COVID-19 infection within 14 days after exposure, defined as a positive respiratory tract specimen for SARS-CoV-2 by polymerase chain reaction. Secondary outcomes include safety, symptomatic COVID-19, seropositivity, hospitalization, respiratory failure requiring ventilator support, mortality, psychological impact, and health-related quality of life. Additional analyses will examine the impact of LPV/r on these outcomes in the subset of participants who test positive for SARS-CoV-2 at baseline. To detect a relative risk reduction of 40% with 80% power at α = 0.05, assuming the secondary attack rate in ring members (p0) = 15%, 5 contacts per case and intra-class correlation coefficient (ICC) = 0.05, we require 110 clusters per arm, or 220 clusters overall and approximately 1220 enrollees after accounting for 10% loss-to-follow-up. We will modify the sample size target after 60 clusters, based on preliminary estimates of p0, ICC, and cluster size and consider switching to an alternative drug after interim analyses and as new data emerges. The primary analysis will be a generalized linear mixed model with logit link to estimate the effect of LPV/r on the probability of infection. Participants who test positive at baseline will be excluded from the primary analysis but will be maintained for additional analyses to examine the impact of LPV/r on early treatment. DISCUSSION: Harnessing safe, existing drugs such as LPV/r as PEP could provide an important tool for control of the COVID-19 pandemic. Novel aspects of our design include the ring-based prevention approach, and the incorporation of remote strategies for conducting study visits and biospecimen collection. TRIAL REGISTRATION: This trial was registered at www.ClinicalTrials.gov ( NCT04321174 ) on March 25, 2020.

Moving fast but going slow: coordination challenges for trials of COVID-19 post-exposure prophylaxis.

An unprecedented volume of research has been generated in response to the COVID-19 pandemic. However, there are risks of inefficient duplication and of important work being impeded if efforts are not synchronized. Excessive reliance on observational studies, which can be more rapidly conducted but are inevitably subject to measured and unmeasured confounders, can foil efforts to conduct rigorous randomized trials. These challenges are illustrated by recent global efforts to conduct clinical trials of post-exposure prophylaxis (PEP) as a strategy for preventing COVID-19. Innovative strategies are needed to help overcome these issues, including increasing communication between the Data Safety and Monitoring Committees (DSMCs) of similar trials. It is important to reinforce the primacy of high-quality trials in generating unbiased answers to pressing prevention and treatment questions about COVID-19.

Protecting Frontline Health Care Workers from COVID-19 with Hydroxychloroquine Pre-exposure Prophylaxis: A structured summary of a study protocol for a randomised placebo-controlled multisite trial in Toronto, Canada.

OBJECTIVES: Primary Objective: To determine if pre-exposure prophylaxis (PrEP) with 400mg hydroxychloroquine (HCQ), taken orally once daily reduces microbiologically confirmed COVID-19 among front line health care workers at high risk for SARS-CoV-2 exposure. Secondary Objectives: To compare the following between study arms: adverse events; symptomatic COVID-19; duration of symptomatic COVID-19; days hospitalized attributed to COVID-19; respiratory failure attributable to COVID-19 requiring i) non-invasive ventilation or ii) intubation/mechanical ventilation; mortality attributed to COVID-19, number of days unable to work attributed to COVID-19, seroconversion (COVID-19 negative to COVID-19 positive over the study period); ability of participant plasma to neutralize SARS-CoV-2 virus in vitro; To describe short-term psychological distress associated with risk of COVID-19 exposure at 1, 60, 120 days of the study. To explore laboratory markers within participants with confirmed COVID-19: including circulating markers of host immune and endothelial activation in participant plasma and their correlation with disease severity and outcome TRIAL DESIGN: The HEROS study is a two-arm, parallel-group, individually randomized (1:1 allocation ratio), placebo controlled, participant and investigator-blinded, multi-site superiority trial of oral HCQ 400 mg taken once daily for 90 days as PrEP to prevent COVID-19 in health care workers at high risk of SARS-CoV-2 exposure. At 90 days, there is an open label extension wherein all participants are offered a one-month course of HCQ 400mg once daily for PrEP of COVID-19. PARTICIPANTS: Frontline HCWs aged 18 years of age or older, at high risk of SARS-CoV-2 exposure (including staff of emergency departments, intensive care units, intubation teams, COVID-wards, and staff deployed to Long Term Care facilities) of five academic hospitals in downtown Toronto, Canada. Exclusion criteria include: currently pregnant, planning to become pregnant during the study period, and/or breast feeding; known hypersensitivity/allergy to hydroxychloroquine or to 4-aminoquinoline compounds; current use of hydroxychloroquine; known prolonged QT syndrome and/or baseline resting ECG with QTc>450 ms and/or concomitant medications which simultaneously may prolong the QTc that cannot be temporarily suspended/replaced; known pre-existing retinopathy, G6PD deficiency, porphyria, liver disease including cirrhosis, encephalopathy, hepatitis or alcoholism, diabetes on oral hypoglycemics or insulin, or renal insufficiency/failure; disclosure of self-administered use of hydroxychloroquine or chloroquine within 12 weeks prior to study; confirmed symptomatic COVID-19 at time of enrollment. INTERVENTION AND COMPARATOR: Intervention: hydroxychloroquine, 400mg (2 tablets) orally per day. Comparator: placebo, two tablets visually identical to the intervention, orally per day MAIN OUTCOMES: The primary outcome is microbiologically confirmed COVID-19 (i.e. SARS-CoV-2 infection). This is a composite endpoint which includes positive results from any validated SARS-CoV-2 diagnostic assay including detection of viral RNA, and/or seroconversion. Participants will be assessed at baseline, and then undergo monthly follow-up at day 30, 60, and 90, 120. At each visit, participants will provide an oropharyngeal sample, blood sample, and will undergo electrocardiogram monitoring of the QTc interval. Secondary outcome measures include: adverse events; symptom duration of COVID-19; days of hospitalization attributed to COVID-19; respiratory failure requiring ventilator support attributed to COVID-19; mortality attributed to COVID-19; total days off work attributed to COVID-19; seropositivity (reactive serology by day 120); and short term psychological impact of exposure to SARS-CoV-2 at day 1, 60, 120 days using the K10, a validated measure of non-specific psychological distress. RANDOMISATION: Within each site, participants will be individually randomized to either the intervention arm with HCQ or the placebo arm using a fixed 1:1 allocation ratio using an interactive web-based response system to ensure concealment of allocation. Randomization schedules will be computer-generated and blocked using variable block sizes. BLINDING (MASKING): All participants, research coordinators, technicians, clinicians and investigators will be blinded to the participant allocation group. Numbers to be randomised (sample size) N=988, randomised into two groups of 494 patients. TRIAL STATUS: This summary describes protocol version No. 1.6, May 15, 2020. Recruitment is ongoing - started April 20, 2020 and anticipated end date is July 30, 2021 TRIAL REGISTRATION: ISRCTN.com Identifier: ISRCTN14326006, registered April 14, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).