Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 12 de 12
Filter
1.
Topics in Antiviral Medicine ; 30(1 SUPPL):17, 2022.
Article in English | EMBASE | ID: covidwho-1881061

ABSTRACT

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.

2.
Topics in Antiviral Medicine ; 30(1 SUPPL):173, 2022.
Article in English | EMBASE | ID: covidwho-1880928

ABSTRACT

Background: The discovery and development of SARS-CoV-2 therapies remains a priority. SAB-185 is a Transchromosomic, bovine-derived, fully human polyclonal immunoglobulin product for SARS-CoV-2 being studied in ACTIV-2, randomized controlled platform trial evaluating the safety and efficacy of investigational agents for non-hospitalized adults with mild-moderate COVID-19 Methods: This Phase II trial was a superiority comparison of SAB-185 vs. placebo. Participants with confirmed SAR-CoV-2 infection received intravenous infusion of SAB-185 (3,840 Units/kg) or placebo. Primary outcome measures were proportion of participants with SARS-CoV-2 RNA < lower limit of quantification (LLoQ) in nasopharyngeal (NP) swab, time to improvement in targeted symptoms for 2 consecutive days after Day 0, and safety through Day 28. Secondary outcomes included quantitative NP RNA levels and all-cause hospitalizations and deaths. Antiviral or clinical efficacy and safety criteria for graduation to Phase III were pre-specified. Results: From April to August 2021, randomized participants from 42 sites in the US received SAB-185 (N=107) or placebo (N=106). Median age was 38 years (quartiles: 30,48), 54% female, >98% cis-gender, 7% Black/African-American, 50% Hispanic, and 11% were classified as high-risk for COVID-19 progression, with median 4 days (3,6) from symptom onset. Day 0 NP SARS-CoV-2 RNA levels were similar between SAB-185 and placebo: 4.80 vs 4.80 log10 copies/ml. No differences were observed in the proportion with NP SARS-CoV-2 RNA< lower limit of quantification (LLoQ) in nasopharyngeal (NP) swab, time to improvement in targeted symptoms for 2 consecutive days after Day 0, and safety through Day 28. Secondary outcomes included quantitative NP RNA levels and all-cause hospitalizations and deaths. Antiviral or clinical efficacy and safety criteria for graduation to phase 3 were pre-specified. Conclusion: SAB-185 was safe in this Phase II study. While no significant differences to placebo were seen in symptom duration and proportion of participants with NP SARS-CoV-2 RNA< lower limit of quantification (LLoQ) in nasopharyngeal (NP) swab, time to improvement in targeted symptoms for 2 consecutive days after Day 0, and safety through Day 28. Secondary outcomes included quantitative NP RNA levels and all-cause hospitalizations and deaths. Antiviral or clinical efficacy and safety criteria for graduation to phase 3 were pre-specified.

3.
Topics in Antiviral Medicine ; 30(1 SUPPL):41, 2022.
Article in English | EMBASE | ID: covidwho-1880388

ABSTRACT

Background: Camostat, a serine protease inhibitor, prevents activation of the SARS-CoV-2 spike protein and blocks SARS-CoV-2 infection in vitro. We studied the safety and antiviral and clinical efficacy of orally administered camostat in non-hospitalized adults with mild-moderate COVID-19. Methods: ACTIV-2/A5401 is a platform trial to evaluate therapies for non-hospitalized adults with mild-moderate COVID-19. In a Phase II portion of the study, participants were enrolled within 10 days of COVID-19 related symptom onset and randomized to camostat 200 mg orally every 6 hours for 7 days or the pooled placebo group. Objectives were to evaluate the safety and efficacy of camostat to reduce the duration of COVID-19 symptoms and increase the proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) from nasopharyngeal (NP) swabs on days 3, 7, and 14. Participants completed a study diary from day 0 to day 28 scoring COVID-19 symptoms as absent, mild, moderate, or severe. Results: Of the 224 participants enrolled from 54 US sites, 215 participants (108 camostat, 107 placebo) initiated study intervention and formed the modified intent-to-treat population. Fifty-four percent were female, >99% cis-gender, 85% White, 9% Black, and 51% Latinx. Median age was 37 years;47% reported ≤5 days of symptoms at study entry and 26% met the protocol definition of higher risk of progression to severe COVID-19. Most frequent symptoms on day 0 were cough (86%), fatigue (85%), nasal obstruction/congestion (71%) and body/muscle aches (71%). There was no significant difference between camostat and placebo arms in grade 3 or higher adverse events (7.4% vs. 6.5%, respectively). Median (Q1, Q3) time to symptom improvement was 9 days for both camostat (5, 20) and placebo (6, 19). There were no significant differences in the proportion of participants with NP SARS-CoV-2 RNA<="" div=""> Conclusion: Camostat was well-tolerated. Despite compelling in vitro data, camostat did not show evidence of antiviral or clinical efficacy in ACTIV-2/A5401. This highlights the critical importance of randomized controlled trials in the evaluation of therapies for COVID-19.

4.
Topics in Antiviral Medicine ; 30(1 SUPPL):246, 2022.
Article in English | EMBASE | ID: covidwho-1880203

ABSTRACT

Background: Randomized COVID-19 trials provide opportunities to describe post-acute sequelae of SARS-CoV-2 (PASC)-related symptom burden longitudinally and assess the impact of early use of antivirals on PASC prevalence. Methods: ACTIV-2 evaluates safety and efficacy of investigational agents for non-hospitalized adults with mild to moderate COVID-19 in a Phase II/III trial. In Phase II, participants were randomized within 10 days of symptom onset and a positive SARS-CoV-2 virologic test to receive bamlanivimab (BAM) or placebo as a single infusion at 7000mg (n=94) or 700mg (n=225). In a subsequent single-arm open-label study, 1059 participants received 700mg BAM. Participants completed a 13-symptom daily diary from enrollment through Day 28. A long-term (LT) diary (14 additional symptoms) introduced after the study was underway was completed by a subset of individuals every 12 weeks. We report Week 24 findings. Results: Between Aug 2020 to Feb 2021 605 participants enrolled and completed LT diary at Week 24 [Phase II: 7000mg vs. placebo (n=25);700mg vs. placebo (n=68);single-arm open-label cohort: 700mg (n=512)]. Median age was 50 years, 51% female sex, 99% identified as cis-gender, 5% Black/African American, and 35% Hispanic/Latino. At enrollment, 53% reported ≥1 high-risk comorbidity and 0.3% were vaccinated against COVID-19. By Week 24, 14% (87/605) had not returned to their pre-COVID-19 health by self-report, with 57% (50/87) reporting ≥3 PASC symptoms. The most common symptoms were fatigue (45% of 87), smell disorder (36%), breathing difficulties (30%), taste disorders (25%), musculoskeletal pain (26%) or weakness (23%), and cognitive complaints: difficulty concentrating/thinking (30%), difficulty reasoning and solving problems (21%), memory loss (25%) and insomnia (23%). Most reported symptoms as "mild". Participants who reported acute viral illness symptoms between Days 22-28 were more likely to report PASC symptoms at Week 24 than those who did not report symptoms at Days 22-28 [51% (164/320) vs. 27% (76/285);p<0.0001]. Conclusion: In outpatients with mild to moderate COVID-19, 14% had not returned to pre-COVID-19 health by 24 weeks post infection, with generally mild but multiple symptoms. Presence of acute viral illness symptoms at 3-4 weeks was associated with an increased risk of PASC symptoms months later. Larger placebo-controlled studies within ACTIV-2 will assess the potential for early antiviral therapies to mitigate or prevent PASC.

5.
Open Forum Infectious Diseases ; 8(SUPPL 1):S807-S808, 2021.
Article in English | EMBASE | ID: covidwho-1746276

ABSTRACT

Background. SARS-CoV-2 continues to spread and the development of safe and effective therapeutics for the prevention of severe disease remains a priority. BRII-196 and BRII-198 are non-competing anti-SARS-CoV-2 mAbs with YTE triple amino acid substitution in Fc to extend half-life and reduce receptor binding, that are being studied for treatment of COVID-19 in the ACTIV-2 Trial, sponsored by NIAID and led by ACTG. Methods. ACTIV-2 evaluates safety/efficacy of investigational agents for treatment of non-hospitalized adults with mild-moderate COVID-19 under a randomized, blinded, controlled adaptive platform. BRII-196/BRII-198 (1000 mg each) as a single dose given as sequential infusions, or placebo to those at high risk of clinical progression (i.e., age ≥ 60 years or presence of other medical conditions) within 10 days of symptom onset and positive test for SARS-CoV-2. The primary endpoint was hospitalization and/or death through day 28. We report Phase 3 BRII-196/BRII-198 trial results per DSMB recommendation following an interim analysis. Results. Between January and July 2021, 837 participants (418 active, 419 placebo) from sites in the US (66%), Brazil, South Africa, Mexico, Argentina and the Philippines were randomized and received study product at time of emerging variants. Median age 49 years (Q1, Q3: 39, 58), 51% female, 17% Black/African-American and 49% Hispanic/Latino, with median 6 days from symptom onset. At interim analysis 71% and 97% had a day 28 and 7 visit, respectively. For all available data at interim review, BRII-196/BRII-198 compared to placebo had fewer hospitalizations (12 vs. 45) and deaths (1 vs. 9). At day 28 of follow-up, there was an estimated 78% reduction in hospitalization and/or death (2.4 vs. 11.1%), relative risk 0.22 (95% CI: 0.05, 0.86), P=0.00001 (nominal one-sided). Grade 3 or higher adverse events (AEs) were observed less frequently among BRII-196/BRII-198 participants than placebo (3.8% vs. 13.4%) with no severe infusion reactions or drug related serious AEs. Conclusion. BRII-196/BRII-198 was safe, well-tolerated, and demonstrated significant reduction compared to placebo in the risk of hospitalization and/or death among adults with mild-moderate COVID-19 at high risk for progression to severe disease.

6.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-329391

ABSTRACT

Background: Easily distributed oral antivirals are urgently needed to treat coronavirus disease-2019 (COVID-19), prevent progression to severe illness, and block transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report the results of a Phase 2a trial evaluating the safety, tolerability, and antiviral efficacy of molnupiravir in the treatment of COVID-19 ( ClinicalTrials.gov NCT04405570 ). Methods: Eligible participants included outpatients with confirmed SARS-CoV-2 infection and symptom onset within 7 days. Participants were randomized 1:1 to 200 mg molnupiravir or placebo, or 3:1 to molnupiravir (400 or 800 mg) or placebo, twice-daily for 5 days. Antiviral activity was assessed as time to undetectable levels of viral RNA by reverse transcriptase polymerase chain reaction and time to elimination of infectious virus isolation from nasopharyngeal swabs. Results: Among 202 treated participants, virus isolation was significantly lower in participants receiving 800 mg molnupiravir (1.9%) versus placebo (16.7%) at Day 3 (p = 0.02). At Day 5, virus was not isolated from any participants receiving 400 or 800 mg molnupiravir, versus 11.1% of those receiving placebo (p = 0.03). Time to viral RNA clearance was decreased and a greater proportion overall achieved clearance in participants administered 800 mg molnupiravir versus placebo (p = 0.01). Molnupiravir was generally well tolerated, with similar numbers of adverse events across all groups. Conclusions: Molnupiravir is the first oral, direct-acting antiviral shown to be highly effective at reducing nasopharyngeal SARS-CoV-2 infectious virus and viral RNA and has a favorable safety and tolerability profile.

7.
MEDLINE;
Preprint in English | MEDLINE | ID: ppcovidwho-326686

ABSTRACT

Resistance mutations to monoclonal antibody (mAb) therapy has been reported, but in the non-immunosuppressed population, it is unclear if in vivo emergence of SARS-CoV-2 resistance mutations alters either viral replication dynamics or therapeutic efficacy. In ACTIV-2/A5401, non-hospitalized participants with symptomatic SARS-CoV-2 infection were randomized to bamlanivimab (700mg or 7000mg) or placebo. Treatment-emergent resistance mutations were significantly more likely detected after bamlanivimab 700mg treatment than placebo (7% of 111 vs 0% of 112 participants, P=0.003). There were no treatment-emergent resistance mutations among the 48 participants who received bamlanivimab 7000mg. Participants with emerging mAb resistant virus had significantly higher pre-treatment nasopharyngeal and anterior nasal viral load. Intensive respiratory tract viral sampling revealed the dynamic nature of SARS-CoV-2 evolution, with evidence of rapid and sustained viral rebound after emergence of resistance mutations, and worsened symptom severity. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest and associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment, resulting in prolonged high level respiratory tract viral loads and clinical worsening. Careful virologic assessment should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19.

9.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-296541

ABSTRACT

Objectives: To define the incidence of clinically-detected COVID-19 in people with HIV (PWH) in the US and evaluate how racial and ethnic disparities, comorbidities, and HIV-related factors contribute to risk of COVID-19. Design: Observational study within the CFAR Network of Integrated Clinical Systems cohort in 7 cities during 2020. Methods: We calculated cumulative incidence rates of COVID-19 diagnosis among PWH in routine care by key characteristics including race/ethnicity, current and lowest CD4 count, and geographic area. We evaluated risk factors for COVID-19 among PWH using relative risk regression models adjusted with disease risk scores. Results: Among 16,056 PWH in care, of whom 44.5% were Black, 12.5% were Hispanic, with a median age of 52 years (IQR 40-59), 18% had a current CD4 count < 350, including 7% < 200;95.5% were on antiretroviral therapy, and 85.6% were virologically suppressed. Overall in 2020, 649 PWH were diagnosed with COVID-19 for a rate of 4.94 cases per 100 person-years. The cumulative incidence of COVID-19 was 2.4-fold and 1.7-fold higher in Hispanic and Black PWH respectively, than non-Hispanic White PWH. In adjusted analyses, factors associated with COVID-19 included female sex, Hispanic or Black identity, lowest historical CD4 count <350 (proxy for CD4 nadir), current low CD4/CD8 ratio, diabetes, and obesity. Conclusions: Our results suggest that the presence of structural racial inequities above and beyond medical comorbidities increased the risk of COVID-19 among PWHPWH with immune exhaustion as evidenced by lowest historical CD4 or current low CD4:CD8 ratio had greater risk of COVID-19.

10.
Topics in Antiviral Medicine ; 29(1):304-305, 2021.
Article in English | EMBASE | ID: covidwho-1250563

ABSTRACT

Background: The emergence of SARS-CoV-2 viral variants threatens current anti-viral and preventative strategies, including monoclonal antibodies and vaccines. Critically, the limited supply of vaccines and the complex logistics surrounding the delivery of infusion-based therapies herald the need for an easily produced, distributed, and specific direct-acting antiviral for COVID-19 that limits progression of illness and ideally prevents transmission. Methods: The efficacy of molnupiravir was evaluated in a double-blind, randomized, placebo-controlled, Phase 2 dose-range finding study using realtime polymerase chain reaction (RT-PCR) and virus isolation was conducted at 11 study sites in the U.S. Participants were randomized if they had signs or symptoms of COVID-19 within 7 days, and a positive SARS-CoV-2 RT-PCR within 4 days of enrollment. Initially, participants were randomized in a 1:1 ratio to receive 200 mg molnupiravir or placebo twice daily for 5 days. Subsequently, in the dose-range finding portion of the study, participants were randomized in a 3:1 ratio to receive 200, 400, or 800 mg molnupiravir or placebo twice daily for 5 days. Nasopharyngeal swabs were analyzed from 175 subjects at enrollment, Day 3, and Day 5 for SARS-CoV-2 infectivity. Samples were stored at 4°C for up to 72 hours, shipped refrigerated, aliquoted, and stored at -80°C until testing. Vero E6 cell monolayers were infected with the sample for 1 hour. Culture medium was analyzed for viral load at 2 and 5 days post-infection by RT-PCR. Results: Seventy-eight (45%) participants, median 4.62 days (min. 1.40, max. 7.54) from symptom onset, had a positive SARS-CoV-2 culture at enrollment (52 on active and 26 on placebo). The percentage of participants with a positive viral culture at enrollment who were positive on Day 3 was 20.4% on active and 28% on placebo (p = 0.56). At day 5, 24% of placebo participants were culturethe positive compared to none treated with molnupiravir (p = 0.001). Between treatment, comparisons were performed using Fisher's exact test. Conclusion: This is the first demonstration of reduced infectiousness by antiviral therapy in people with SARS-2 infection. This simple, short-course oral therapy may benefit individuals and public health and is unlikely to be impacted by spike-protein variants.

11.
Topics in Antiviral Medicine ; 29(1):210-211, 2021.
Article in English | EMBASE | ID: covidwho-1250023

ABSTRACT

Background: The relationship between nasopharyngeal (NP) SARS-CoV-2 RNA, demographics and symptom characteristics in non-hospitalized persons with COVID-19 is not well described. Methods: ACTIV-2 is a phase 2/3 adaptive platform trial testing antivirals for SARS-CoV-2 in symptomatic non-hospitalized adults. We analyzed associations between NP quantitative SARS-CoV-2 RNA (Abbott m2000sp/rt) and COVID-19 symptomatology in 284 participants with both a NP swab and symptom diary prior to study intervention. The diary included 13 targeted symptoms and questions about overall severity of COVID-19 symptoms, each scored as none, mild, moderate, or severe (and very severe for overall severity) and general physical health (scored as poor, fair, good, very good, excellent). Wilcoxon tests were used to compare NP RNA levels between pre-defined groups. Spearman correlations, Jonchkeere-Terpstra trend tests, and linear regressions evaluated associations between symptom measures and NP RNA. Results: Participants were 49% female, 82% white, 9% black, and 27% Latinx. Median age was 46 years and 50% met the protocol definition of higher risk for COVID-19 progression (age ≥55 years and/or protocol-defined comorbidities);32% reported moderate and 5% severe symptoms. Median (Q1, Q3) time from onset of symptoms to NP swab/symptom assessment was 6 (4, 8) days. NP RNA was above the lower limit of quantification in 85%;median (Q1, Q3) was 5.4 (3.5, 6.8) log10 copies/mL. Higher RNA levels were associated with shorter symptom duration (median 6.5 vs 4.7 log10 copies/mL for ≤5 vs >5 days) but not total symptom score (Figure). Controlling for symptom duration, higher NP RNA levels were associated with better general physical health (p=0.02) and more severe body/muscle pain (p=0.04). No associations were observed with symptom severity (sum of scores or overall severity) or any other symptoms. There was no association between NP RNA and age or risk category for COVID-19 progression. Conclusion: In symptomatic outpatients, NP SARS-CoV-2 RNA levels were higher in persons with more recent symptom onset, but were not associated with symptom severity or risk for disease progression. The range of viral RNA shedding was remarkably similar across the range of symptom severity, suggesting symptom severity may not correlate with transmission risk or the potential to respond to antiviral therapy. Outpatient trials aimed at evaluating antiviral activity of new agents should focus enrollment on participants with recent onset of symptoms. (Figure Presented).

12.
Topics in Antiviral Medicine ; 29(1):140-141, 2021.
Article in English | EMBASE | ID: covidwho-1250022

ABSTRACT

Background: Due to the substantial morbidity but low rates of hospitalization and death among outpatients with COVID-19, symptom outcome measures should be considered for primary efficacy assessment in phase 3 treatment trials. We analyzed potential measures utilizing the ACTIV-2 participant diary. Methods: Data from the first 95 participants in ACTIV-2 were included. All had symptomatic SARS-CoV-2 infection and received blinded bamlanivimab 7000 mg/placebo. The symptom diary was completed by participants prior to treatment (Day 0) and then daily for 28 days. It included 13 targeted symptoms scored as absent, mild, moderate, or severe, and a question about whether they had returned to pre-COVID-19 health. Without unblinding, 3 candidate symptom outcome measures were assessed: A) time to confirmed (2 consecutive days) absence of all targeted symptoms, B) time to all targeted symptoms confirmed to be mild or absent, and C) time to confirmed improvement in all targeted symptoms. Median time to outcome was estimated by Kaplan-Meier methods. Results: Of the 95 participants, 53% were female, 82% white, and 33% Latinx. Median age was 44 years;46% were age ≥55 years and/or had protocol-defined comorbidities. Median time from COVID-19 symptom onset to randomization was 6 days. Prevalence of each targeted symptom on Day 0 ranged from 6% vomiting to 87% fatigue. Candidate outcome B was met in median 2 days due to 29% of participants having only mild symptoms at Day 0. For candidate outcomes A and C, median time was 11 and 8 days, with 26% and 16%, respectively, not meeting the outcome by 28 days. These candidate outcomes (A and C) were associated with a participant's confirmed assessment of return to pre-COVID-19 health (Figure). For all measures, increasing the consecutive days required for confirmation from 2 to 3 or 4 had a modest impact on median time to the outcome being met, consistent with few participants experiencing relapsing symptoms. Conclusion: Outcomes based on symptom resolution (A) or improvement (C) are promising for evaluating COVID-19 treatment response, with good internal validity with self-assessment of return to pre-COVID-19 health. A valid symptom outcome measure may be preferred over hospitalization/death as a primary outcome for outpatient COVID-19 treatment trials as most participants achieve the outcome, increasing power to compare treatments, especially among participants who are at low risk for hospitalization/death.

SELECTION OF CITATIONS
SEARCH DETAIL