Publications by authors named "Michael E Abram"

Article Synopsis
  • * Analysis showed that RSV A and B infections occurred at similar rates, with some noteworthy substitutions in their fusion proteins affecting susceptibility to nirsevimab.
  • * Despite some binding site changes, over 99% of RSV isolates from the trials remained sensitive to nirsevimab, indicating its continued effectiveness.
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Article Synopsis
  • - Nirsevimab is a monoclonal antibody designed to protect infants from respiratory syncytial virus (RSV) by maintaining high levels of neutralizing antibodies (NAbs) after administration, as shown in the MELODY clinical trials.
  • - Analysis of over 2,000 infants revealed that preterm infants had lower baseline RSV antibody levels compared to full-term infants, but nirsevimab significantly boosted NAb levels, remaining high for up to a year.
  • - Despite its protective effects against RSV, nirsevimab still allowed infants to develop their immune response to the virus, indicating it can both prevent RSV disease and promote future immunity.
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  • Nirsevimab, a long-lasting monoclonal antibody developed to protect infants from RSV, shows great potential due to the high conservation of its binding site, although the emergence of escape variants needs further investigation from 2015 to 2021.
  • The study analyzed RSV A and B prevalence across multiple global surveillance studies, revealing that most amino acids in the nirsevimab binding site remained stable, with only a notable polymorphism (Ile206Met:Gln209Arg) appearing in RSV B after 2016.
  • The researchers found that nirsevimab effectively neutralizes various RSV strains, including some with binding-site changes, although certain RSV B variants showed reduced sensitivity to nirsevim
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AZD7442, a combination of two long-acting monoclonal antibodies (tixagevimab [AZD8895] and cilgavimab [AZD1061]), has been authorized for the prevention and treatment of coronavirus disease 2019 (COVID-19). The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants requires methods capable of quickly characterizing resistance to AZD7442. To support AZD7442 resistance monitoring, a biolayer interferometry (BLI) assay was developed to screen the binding of tixagevimab and cilgavimab to SARS-CoV-2 spike proteins to reduce the number of viral variants for neutralization susceptibility verification.

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Article Synopsis
  • Respiratory syncytial virus (RSV) significantly affects infants, leading to serious lower respiratory infections, and nirsevimab is a monoclonal antibody designed to combat this infection.
  • In a study involving 1490 infants, those receiving nirsevimab showed a 74.5% effectiveness in preventing medically attended RSV-associated infections compared to the placebo group.
  • The results indicate that while nirsevimab reduced the incidence of RSV-related complications, the overall rate of serious adverse events was similar between the nirsevimab and placebo groups, suggesting a reasonable safety profile for the treatment.
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Background: More than 2 million SARS-CoV-2 genome sequences have been generated and shared since the start of the COVID-19 pandemic and constitute a vital information source that informs outbreak control, disease surveillance, and public health policy. The Pango dynamic nomenclature is a popular system for classifying and naming genetically-distinct lineages of SARS-CoV-2, including variants of concern, and is based on the analysis of complete or near-complete virus genomes. However, for several reasons, nucleotide sequences may be generated that cover only the spike gene of SARS-CoV-2.

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Article Synopsis
  • Despite the success of COVID-19 vaccines, there is still a need for additional prevention and treatment methods for at-risk individuals.
  • AZD7442 is a combination of two monoclonal antibodies that target different parts of the SARS-CoV-2 spike protein, effectively neutralizing the virus and preventing its entry into human cells.
  • Clinical studies suggest that AZD7442 can provide long-lasting protection, potentially up to 12 months, especially benefiting those at higher risk for severe COVID-19 outcomes.
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Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among infants and young children, resulting in annual epidemics worldwide. INFORM-RSV is a multiyear clinical study designed to describe the global molecular epidemiology of RSV in children under 5 years of age by monitoring temporal and geographical evolution of current circulating RSV strains, F protein antigenic sites, and their relationships with clinical features of RSV disease. During the pilot season (2017-2018), 410 RSV G-F gene sequences were obtained from 476 RSV-positive nasal samples collected from 8 countries (United Kingdom, Spain, The Netherlands, Finland, Japan, Brazil, South Africa, and Australia).

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Article Synopsis
  • Respiratory syncytial virus (RSV) is a significant cause of severe respiratory illness in infants, and the INFORM study aims to explore the global molecular diversity of RSV through a comprehensive clinical research approach.
  • The study covers 17 countries across all continents and plans to analyze over 4,000 RSV-positive samples over five years to identify geographical and temporal molecular patterns.
  • Findings will help assess resistance to new treatments and create a database and repository for RSV strains to aid future research and interventions.
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The development of resistance to human immunodeficiency virus 1 (HIV-1) integrase strand-transfer inhibitors (INSTI) has been documented; however, knowledge of the impact of pre-existing integrase (IN) mutations on INSTI resistance (INSTI-R) is still evolving. The frequency of HIV-1 IN mutations in 2177 treatment-naïve subjects was investigated, along with the INSTI susceptibility of site-directed mutant viruses containing major and minor INSTI-R mutations. Total 6 of 39 minor INSTI-R mutations (M50I, S119P/G/T/R, and E157Q) were found in >1% of IN-treatment-naïve subjects with no impact on INSTI susceptibility.

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Background: The presence of transmitted drug resistance mutations (TDRMs) in antiretroviral treatment (ART)-naive patients can adversely affect the outcome of ART.

Methods: Resistance testing was conducted in 6704 ART-naive subjects predominantly from the United States and Europe in 9 clinical studies conducted by Gilead Sciences from 2000 to 2013.

Results: The presence of TDRMs increased during this period (from 5.

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Background: FTC/TAF was shown to be noninferior to FTC/TDF with advantages in markers of renal and bone safety.

Objective: To evaluate the efficacy and safety of switching to FTC/TAF from FTC/TDF by third agent (boosted protease inhibitor [PI] vs. unboosted third agent).

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In a double-blind, phase 3 trial, 663 HIV-infected, virologically suppressed adults were randomized to switch to tenofovir alafenamide (TAF; n = 333) vs. remain on tenofovir disoproxil fumarate (TDF; n = 330), each coformulated with emtricitabine (FTC), while continuing their third agent (boosted protease inhibitor or unboosted third agent). At week 96, 88.

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T97A is an HIV-1 integrase polymorphism associated with integrase strand transfer inhibitor (INSTI) resistance. Using pooled data from 16 clinical studies, we investigated the prevalence of T97A (pre-existing and emergent) and its impact on INSTI susceptibility and treatment response in INSTI-naive patients who enrolled on elvitegravir (EVG)- or raltegravir (RAL)-based regimens. Prior to INSTI-based therapy, primary INSTI resistance-associated mutations (RAMs) were absent and T97A pre-existed infrequently (1.

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Tenofovir disoproxil fumarate is associated with renal and bone toxicity. In a single-arm, open-label study of 242 virologically suppressed, HIV-infected participants with creatinine clearance 30-69 mL/min who switched to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, participants had stable creatinine clearance, significant and durable improvements in proteinuria, albuminuria, and tubular proteinuria (P < 0.001), and significant increases in hip and spine bone mineral density through 96 weeks (P < 0.

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Background: Emtricitabine with tenofovir disoproxil fumarate is a standard-of-care nucleoside reverse transcriptase inhibitor (NRTI) backbone. However, tenofovir disoproxil fumarate is associated with renal and bone toxic effects; the novel prodrug tenofovir alafenamide achieves 90% lower plasma tenofovir concentrations. We aimed to further assess safety and efficacy of fixed-dose combination emtricitabine with tenofovir alafenamide in patients switched from emtricitabine with tenofovir disoproxil fumarate.

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Background: Tenofovir alafenamide (TAF) is a novel tenofovir prodrug with improved renal and bone safety compared with TDF-containing regimens. We report the 48 week safety and efficacy of a once-daily single tablet regimen of elvitegravir 150 mg (E), cobicistat 150 mg (C), emtricitabine 200 mg (F), and TAF 10 mg (E/C/F/TAF) in HIV-1-infected patients with mild to moderate renal impairment.

Methods: We enrolled virologically suppressed HIV-1-infected subjects with estimated creatinine clearance (CrCl) 30-69 mL/min in a single-arm, open-label study to switch regimens to E/C/F/TAF.

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Background: Cobicistat (COBI) is a pharmacoenhancer with no antiretroviral activity.

Methods: International, randomized double-blind active-controlled trial to evaluate the efficacy and safety of COBI vs ritonavir (RTV) as a pharmacoenhancer of atazanavir in combination with emtricitabine/tenofovir disoproxil fumarate in HIV treatment-naive patients followed through week 144.

Results: At Week 144, virologic suppression was achieved in 72% (COBI) and 74% (RTV) of patients.

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Background: Stably suppressed HIV-1-infected patients that switched to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) from regimens containing FTC/TDF plus a ritonavir-boosted protease inhibitor (PI + RTV), nonnucleoside reverse transcriptase inhibitor (NNRTI), or raltegravir in phase 3 studies STRATEGY-PI, STRATEGY-NNRTI, and GS-US-236-0123 maintained high rates of virologic suppression through 48 weeks. In this article, resistance analyses for these studies are described.

Methods: HIV-1 historical genotypes obtained before therapy initiation were analyzed for preexisting/transmitted resistance (-R) in protease and reverse transcriptase (RT) and subtype.

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In HIV-1-infected treatment-naive patients with mild-to-moderate renal impairment [creatinine clearance (CrCl): 50-89 mL/min], elvitegravir/cobicistat/emtricitabine/tenofovir DF (STB, n = 33) achieved high rates of virologic success (78.8%; 95% confidence interval: 61.1% to 91.

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Background: Cobicistat (COBI) is a pharmacoenhancer that optimizes systemic exposures of protease inhibitors (PIs) such as atazanavir (ATV) and darunavir (DRV).

Objective: To evaluate the efficacy and safety of switching ritonavir (RTV) to COBI in patients with creatinine clearance (CrCl) 50 to 89 mL/min who are virologically suppressed on a stable regimen containing ritonavir (RTV)-boosted ATV or DRV. Other components of the regimen remained unchanged.

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During HIV-1 reverse transcription, there are increasing opportunities for nucleos(t)ide (NRTI) or nonnucleoside (NNRTI) reverse transcriptase (RT) inhibitors to stop elongation of the nascent viral DNA (vDNA). In addition, RT inhibitors appear to influence the kinetics of vDNA synthesis differently. While cell-free kinetic inhibition constants have provided detailed mechanistic insight, these assays are dependent on experimental conditions that may not mimic the cellular milieu.

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Objective: To describe baseline and emergent HIV-1 resistance to elvitegravir/ cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF) and ritonavir-boosted atazanavir/emtricitabine/tenofovir DF (ATV+RTV+FTC/TDF) in HIV-1-infected, treatment-naïve subjects through 144 weeks.

Method: This was a randomized, double-blind, phase 3 study. HIV-1 protease (PR) and reverse transcriptase (RT) were sequenced at screening.

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