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Background: Knowing the true incidence of HIV-1 infections (recent infections) among people newly diagnosed is pivotal to monitoring the course of the epidemic. We have developed a Primer ID Next Gen Sequencing (PID-NGS) assay to identify recent infection by measuring within-host viral diversity over multiple regions of the HIV-1 genome. We implemented a state-wide project to identify recent infections and transmitted drug resistance mutations (DRMs) in diagnostic samples in near real time. Methods: Serum samples from individuals with newly HIV-1 diagnoses (diagnostic sample collected within 30 days of diagnosis) were sequenced. PID-NGS libraries were constructed covering the coding regions for protease, a portion of reverse transcriptase, integrase, and the env gene. The use of the PID-NGS strategy allows for significant error correction and also a definition of the sampling depth of the viral population. Recent infection was defined as within 9-month of infection. DRMs were summarized at detection sensitivities of 30%, 10% and 1% based on viral population sampling depth. Results: From Jan 2018 to Jun 2021, we successfully sequenced partial genomes from 743 individuals with new diagnoses. Year 2020 had the lowest number of new diagnoses (Fig 1a, red bar). Overall, 39.2% of samples were inferred to have represented infection within the previous 9 months. Percent of recent infection varied significantly over the years, increasing from 29.6% in late 2018 to 50.9% in early 2020, but decreasing significantly to 32.7% in 2021 (Fig 1a, blue lines). Individuals younger than 30 y/o were more likely to be identified with recent infection (p<0.01). NNRTI DRMs, especially K103N, were the most abundant DRMs. Fig 1b shows the trend of DRMs over the four years. We observed a trend of decrease in the overall NNRTI DRMs and an increase in the NRTI DRMs in the population. Further analysis suggests that the increase in NRTI DRMs were from TAMs and their revertants, while clinically important NRTI DRMs (K65R and M184) were low (<1%). Conclusion: We have demonstrated a state-wide, all-in-one platform to monitor HIV-1 recency and DRMs in new diagnoses. The number of new diagnoses decreased significantly in 2020 in concert with the COVID-19 pandemic which suggests a decrease in overall HIV testing. The decline in the percentage of recent infections in early 2021 signals a return to broader HIV-1 testing and diagnosis. The increase of other NRTI DRMs suggests ongoing evolution at these sites within the viral population.
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Background:A previous report showed that a single 1200 mg subcutaneous (SC) dose of casirivimab and imdevimab (cas/imd) prevented symptomatic COVID-19 by 81.4% and reduced all SARS-CoV-2 infections (symptomatic and asymptomatic) by 66.4% in household contacts living with recently infected individuals over a 28-day period. While highly effective vaccines now exist for the prevention of COVID-19, a significant unmet need remains in patients who are unable to mount or maintain an adequate immune response to vaccination. Here we present additional results from 7-month follow-up period of the aforementioned study. Methods: In this randomized, double-blind, placebo-controlled Phase III trial, asymptomatic participants exposed to a SARS-CoV-2-infected household member were randomized 1:1 to a single SC dose of placebo or 1200 mg cas/imd (600 mg of each monoclonal antibody). Efficacy analyses include participants who were RT-qPCR negative for SARS-CoV-2 (no current infection) and seronegative for SARS-CoV-2 (no prior infection) at baseline. The trial consisted of a primary efficacy assessment period of 28 days (Month 1) and a 7-month follow-up period (Months 2-8). Results: Results from 842 placebo and 841 cas/imd RT-qPCR negative/seronegative enrolled participants (data through 04Oct2021, prior to emergence of Omicron) are presented. During the entirety of the 8-month study, cas/imd reduced the risk of symptomatic SARS-CoV-2 infections by 81.2% versus placebo (nominal P<0.0001;Table) and all SARS-CoV-2 infections (symptomatic and asymptomatic) by 68.2% versus placebo (nominal P<0.0001;Table). During Months 2-5, the risk of symptomatic and all infections were reduced by 100% and 89.5%, respectively (nominal P<0.0001). During Months 6-8 there was a resumption of symptomatic and all SARS-CoV-2 infections in the cas/imd group (19.9%;nominal P=0.6411 and 30.7%;nominal P=0.3967 risk reduction, respectively). Fewer cas/imd participants had a medically-attended visit versus placebo during the 8-months (1/841 [0.1%] vs 16/842 [1.9%], respectively). No new safety signals were identified for cas/imd during the follow-up period. Conclusion: During the 8-month study period, a 1200 mg SC dose of cas/imd prevented SARS-CoV-2 infections, with maximal protection through Month 5. The prolonged protection supports the use of cas/imd for the long-term prevention of COVID-19 against susceptible variants, offering a pre-exposure prophylaxis strategy for individuals who are unlikely to respond or be protected by vaccination.
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Introduction: COVID-19 has created experiential barriers for surgical learners to interact at the bedside for teaching/case presentations. We hypothesized that an international Grand Rounds using the Microsoft HoloLens2 extended reality (XR) headset creates an improved bedside-learning experience compared with traditional Grand Rounds formats. Methods: In December 2020, we hosted (through partnership with the University of Michigan and Imperial College of London) the world’s first International Grand Rounds experience using the HoloLens2 XR headset broadcasting transatlantic bedside rounding on 3 complex surgical patients to an international audience of 154 faculty, residents, and medical trainees. Participants completed qualitative pre- and post-event surveys. Results: Of the 154 participants, 96 (62%) completed pre-surveys and 70 (45%) completed both the pre-and post-surveys. Respondents (average age 39.3 years [43% women;57% men;80 US;16 UK]) included 30 medical students, 30 faculty, 7 residents, and 29 hospital administrators. Pre-event survey: 76% had little or no experience before with XR devices;92% thought development/implementation of XR medical curricula was valuable;and 96% felt tele-rounding using XR technology was important for the current era. Post survey: 98% respondents thought the ability to visualize bedside clinical findings, imaging, and lab-tests via XR rounding was highly valuable and this novel XR international Grand Rounds format was superior to traditional Grand Rounds. Conclusion: Almost all (98%) participants in the world’s first International Grand Rounds on a Mixed Reality Headset felt this immersive extended reality virtual experience allowed visualization of clinical findings, imaging, and labs at the patient’s bedside and was superior to a traditional Grand Rounds format.
ABSTRACT
Importance Preventive interventions are needed to protect residents and staff of skilled nursing and assisted living facilities from COVID-19 during outbreaks in their facilities. Bamlanivimab, a neutralizing monoclonal antibody against SARS-CoV-2, may confer rapid protection from SARS-CoV-2 infection and COVID-19. Objective To determine the effect of bamlanivimab on the incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities. Design, Setting, and Participants Randomized, double-blind, single-dose, phase 3 trial that enrolled residents and staff of 74 skilled nursing and assisted living facilities in the United States with at least 1 confirmed SARS-CoV-2 index case. A total of 1175 participants enrolled in the study from August 2 to November 20, 2020. Database lock was triggered on January 13, 2021, when all participants reached study day 57. Interventions Participants were randomized to receive a single intravenous infusion of bamlanivimab, 4200 mg (n = 588), or placebo (n = 587). Main Outcomes and Measures The primary outcome was incidence of COVID-19, defined as the detection of SARS-CoV-2 by reverse transcriptase-polymerase chain reaction and mild or worse disease severity within 21 days of detection, within 8 weeks of randomization. Key secondary outcomes included incidence of moderate or worse COVID-19 severity and incidence of SARS-CoV-2 infection. Results The prevention population comprised a total of 966 participants (666 staff and 300 residents) who were negative at baseline for SARS-CoV-2 infection and serology (mean age, 53.0 [range, 18-104] years;722 [74.7%] women). Bamlanivimab significantly reduced the incidence of COVID-19 in the prevention population compared with placebo (8.5% vs 15.2%;odds ratio, 0.43 [95% CI, 0.28-0.68];P < .001;absolute risk difference, -6.6 [95% CI, -10.7 to -2.6] percentage points). Five deaths attributed to COVID-19 were reported by day 57;all occurred in the placebo group. Among 1175 participants who received study product (safety population), the rate of participants with adverse events was 20.1% in the bamlanivimab group and 18.9% in the placebo group. The most common adverse events were urinary tract infection (reported by 12 participants [2%] who received bamlanivimab and 14 [2.4%] who received placebo) and hypertension (reported by 7 participants [1.2%] who received bamlanivimab and 10 [1.7%] who received placebo). Conclusions and Relevance Among residents and staff in skilled nursing and assisted living facilities, treatment during August-November 2020 with bamlanivimab monotherapy reduced the incidence of COVID-19 infection. Further research is needed to assess preventive efficacy with current patterns of viral strains with combination monoclonal antibody therapy. This randomized clinical trial assesses the effect of a single intravenous infusion of bamlanivimab vs placebo on incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities. Question Among residents and staff of skilled nursing and assisted living facilities with high risk of SARS-CoV-2 exposure, what is the effect of bamlanivimab on the incidence of COVID-19? Findings This randomized phase 3 clinical trial included 966 participants who were residents and staff at US skilled nursing and assisted living facilities with at least 1 confirmed SARS-CoV-2 index case and who were negative at baseline for SARS-CoV-2 infection and serology, enrolled from August to November 2020. The incidence of COVID-19 infection among those treated with bamlanivimab vs placebo was 8.5% vs 15.2%, respectively, a difference that was statistically significant. Meaning Bamlanivimab monotherapy compared with placebo reduced the risk of COVID-19 in residents and staff of skilled nursing and assisted living facilities.
ABSTRACT
Background: Passive immunization has a long history for infection prevention following exposure. We report results of a descriptive interim analysis from a study of an antibody “cocktail” of casirivimab with imdevimab (cas/imdev;formerly REGN-COV2) designed to bind non-competing epitopes of the viral spike protein, as a potential passive vaccine for the prevention of COVID-19 in people at risk of infection from household contact. Methods: In this ongoing Phase 3 study, asymptomatic participants exposed to a COVID-19-infected household member were randomized 1:1 to placebo or 1200 mg cas/imdev (600 mg of each antibody administered subcutaneously) within 96 hours of their household member testing positive. The analysis included participants who tested negative for SARS-CoV-2 by nasal, saliva, or nasopharyngeal swab and who were seronegative to SARS-CoV-2 antibodies at baseline. The proportion of participants who developed an RT-PCR-confirmed SARS-CoV-2 infection (asymptomatic or symptomatic) during the 1-month efficacy assessment period was summarized. Results: Initial results from the first evaluable 223 placebo and 186 cas/imdev participants who completed ≥29 days of the study are reported. Reduction in PCR-positive symptomatic disease was 100% (0/186 cas/imdev vs 8/223 placebo;OR 0.00 [CI 0.00, 0.69]). Reduction in any PCR-positive infection (symptomatic or asymptomatic) was 48% (10/186 vs 23/223;OR 0.49 [CI 0.20, 1.12]). Placebo-group participants had on average 100-fold higher peak viral load. In the cas/imdev group, viral RNA was not detected for longer than 1 week but was detected for 3-4 weeks in approximately 40% of placebo participants (Fig. 1). The proportions of infected participants with high viral loads (>10 4 copies/mL) were 13/21 placebo vs 0/9 cas/imdev. Total weeks of viral RNA detection and high viral load were 44 and 22 weeks in the placebo group vs 9 and 0 in the cas/imdev group. Total symptomatic weeks were 21 for placebo vs 0 for cas/imdev. A similar proportion of participants experienced at least 1 serious adverse event: placebo, 3/222 and cas/imdev, 1/186;none were deemed related to study treatment. Injection site reactions were similar: placebo, 1.4%;cas/ imdev, 2.6%. Conclusion: In this descriptive interim analysis of participants at risk of SARSCoV- 2 infection from household transmission, a subcutaneous dose of the cas/ imdev antibody cocktail prevented symptomatic infection, reduced overall infection, and decreased viral load and duration of viral RNA detection.
ABSTRACT
Background: The COVID-19 pandemic has disproportionately affected residents of skilled nursing and assisted living facilities. Interventions are urgently needed to protect this vulnerable population. Bamlanivimab is a potent neutralizing monoclonal antibody that binds the receptor-binding domain of the spike protein of SARS-CoV-2. This study evaluates the safety and efficacy of bamlanivimab in preventing COVID-19. Methods: BLAZE-2 is a Phase 3, randomized, double-blind, placebo-controlled, single-dose study that enrolled residents and staff at skilled nursing and assisted living facilities reporting at least one confirmed SARS-CoV-2 case. Eligible participants received bamlanivimab (4200 mg) or placebo intravenously. Nasal swabs were collected at baseline and weekly through day 57 to determine SARS-CoV-2 infection status via reverse transcriptase polymerase chain reaction (RT-PCR). COVID-19-releated symptoms and signs were recorded daily. The primary analysis prevention population included participants negative at baseline for SARS-CoV-2 by RT-PCR and serology. The primary endpoint was incidence of mild or worse COVID-19 by day 57. Results: Of the 1175 participants dosed, 966 (82.2%) comprised the prevention population. The prevention population included 299 residents for whom the median age was 76 years (range 31-104), 234 (78.3%) were aged ≥65, and 178 (59.5%) were female. All were considered at high risk for development of severe COVID-19. The proportion of residents in the prevention population with mild or worse COVID-19 by day 57 was significantly lower in the bamlanivimab group compared with the placebo group (odds ratio [OR], 0.20;95% confidence interval [CI], 0.08 to 0.49;p<0.001)(Figure). For this same group, bamlanivimab was associated with significant reductions in the incidence of moderate or worse COVID-19 by day 57 (OR, 0.20;95% CI, 0.08 to 0.49;p<0.001) and incident SARS-CoV-2 infection by day 29 (OR, 0.23;CI, 0.11 to 0.48;p<0.001) compared with placebo. Of the 16 deaths reported during the study, all 5 that were attributed to COVID-19 were in the placebo group. The incidence of both adverse events and serious adverse events were balanced between the bamlanivimab and placebo group. Conclusion: Bamlanivimab was highly effective in reducing the incidence of symptomatic COVID-19 and SARS-CoV-2 infection and was well tolerated. These findings demonstrate the potential beneficial impact of bamlanivimab use on COVID-19 morbidity and mortality among skilled nursing facility residents.