scholarly journals HIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase Mutants

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Steven J. Smith ◽  
Xue Zhi Zhao ◽  
Dario Oliveira Passos ◽  
Dmitry Lyumkis ◽  
Terrence R. Burke ◽  
...  
Keyword(s):  
Strand Transfer ◽  
First Line ◽  
Preclinical Development ◽  
First Line Therapy ◽  
Line Therapy ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Resistant Mutants ◽  
Hiv 1

ABSTRACT The currently recommended first-line therapy for HIV-1-infected patients is an integrase (IN) strand transfer inhibitor (INSTI), either dolutegravir (DTG) or bictegravir (BIC), in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). Both DTG and BIC potently inhibit most INSTI-resistant IN mutants selected by the INSTIs raltegravir (RAL) and elvitegravir (EVG). BIC has not been reported to select for resistance in treatment-naive patients, and DTG has selected for a small number of resistant viruses in treatment-naive patients. However, some patients who had viruses with substitutions selected by RAL and EVG responded poorly when switched to DTG-based therapies, and there are mutants that cause a considerable decrease in the potencies of DTG and BIC in in vitro assays. The new INSTI cabotegravir (CAB), which is in late-stage clinical trials, has been shown to select for novel resistant mutants in vitro. Thus, it is important to develop new and improved INSTIs that are effective against all the known resistant mutants. This led us to test our best inhibitors, in parallel with DTG, BIC, and CAB, in a single-round infection assay against a panel of the new CAB-resistant mutants. Of the INSTIs we tested, BIC and our compound 4d had the broadest efficacy. Both were superior to DTG, as evidenced by the data obtained with the IN mutant T66I/L74M/E138K/S147G/Q148R/S230N, which was selected by CAB using an EVG-resistant lab strain. These results support the preclinical development of compound 4d and provide information that can be used in the design of additional INSTIs that will be effective against a broad spectrum of resistant mutants.

scholarly journals Inhibition of platelet phagocytosis as an in vitro predictor for therapeutic potential of RBC antibodies in murine ITP

Blood ◽  
2020 ◽  
Vol 135 (26) ◽  
pp. 2420-2424 ◽  
Author(s):  
Ramsha Khan ◽  
Melissa Menard ◽  
Chao-Ching Jen ◽  
Xi Chen ◽  
Peter A. A. Norris ◽  
...  
Keyword(s):  
Blood Cells ◽  
Immune Thrombocytopenia ◽  
Therapeutic Potential ◽  
Sufficient Condition ◽  
First Line ◽  
Phagocytosis Assay ◽  
First Line Therapy ◽  
Line Therapy

Abstract Polyclonal anti-D is a first-line therapy for immune thrombocytopenia (ITP). Monoclonal antibodies are desirable alternatives, but none have yet proven successful despite their ability to opsonize erythrocytes (or red blood cells, RBCs) and cause anemia. Here, we examined 12 murine erythrocyte–specific antibodies of different specificity and subtypes and found that 8 of these antibodies could induce anemia in antigen-positive mice. Of these 8 antibodies, only 5 ameliorated ITP. All antibodies were examined for their in vitro ability to support macrophage-mediated phagocytosis of erythrocytes. Antibodies which supported erythrocyte phagocytosis in vitro successfully ameliorated ITP in vivo. To examine the ability of each antibody to inhibit phagocytosis of platelets, the antibodies were used to sensitize erythrocytes in vitro and these were added to a platelet phagocytosis assay. Antibodies that inhibited platelet phagocytosis in vitro also all ameliorated ITP in vivo. We conclude that inducing anemia is not a sufficient condition for amelioration of ITP but that the antibody’s ability to prevent platelet phagocytosis in vitro predicted its ability to ameliorate ITP. We suggest that inhibition of in vitro platelet phagocytosis may prove to be a valuable tool for determining which erythrocyte antibodies would likely be candidates for clinical use in ITP.

scholarly journals Immune and virologic responses to Truvada or Combivir as a first-line therapy of HIV-infected, treatment-naïve patients

2008 ◽  
Vol 11 (Suppl 1) ◽  
pp. P206
Author(s):  
R Maserati ◽  
M Clerici ◽  
M Lauriola ◽  
M Pacei ◽  
M De Gennaro ◽  
...  
Keyword(s):  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Treatment Naïve

scholarly journals 1360. Antimicrobial Activity of Cefepime in Combination with VNRX-5133 Against a Global Collection of Enterobacteriaceae Including Resistant Phenotypes

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S416-S417 ◽  
Author(s):  
Meredith Hackel ◽  
Dan Sahm
Keyword(s):  
Vitro Activity ◽  
In Vitro Activity ◽  
First Line ◽  
First Line Therapy ◽  
Carbapenem Resistant ◽  
Line Therapy ◽  
Resistant Strains ◽  
Further Development ◽  
Dose Dependent

Abstract Background VNRX-5133 is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor with potent and selective direct inhibitory activity against both serine- and metallo-β-lactamases (Ambler Classes A, B, C, and D). In this analysis, we evaluated the activity of cefepime (FEP) in combination with VNRX-5133 and comparators against 1,120 recent Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Methods MICs of FEP with VNRX-5133 fixed at 4 µg/mL (FEP/VNRX-5133) were determined following CLSI M07-A10 guidelines against 1,120 Enterobacteriaceae from community and hospital infections collected globally in 2012–2013. Resistant phenotypes were based on 2017 CLSI breakpoints. As FEP/VNRX-5133 breakpoints have not yet been established, the FEP 2 g q8h susceptible dose-dependent (SDD) breakpoint of ≤8 µg/mL was considered for comparative purposes. Results FEP/VNRX-5133 showed potent in vitro activity against drug-resistant subsets of Enterobacteriaceae, with MIC90 values ranging from 1 µg/mL against ceftazidime-, levofloxacin-, or piperacillin–tazobactam-nonsusceptible isolates, to 8 µg/mL against meropenem-nonsusceptible isolates. FEP/VNRX-5133 inhibited >93% of all resistant subsets at ≤8 µg/mL. Conclusion Cefepime in combination with VNRX-5133 demonstrated potent in vitro activity against Enterobacteriaceae, including cephalosporin-, fluoroquinolone- and carbapenem-resistant (CRE) isolates. Because this drug combination exhibited substantial potential for the treatment of infections caused by isolates often resistant to first-line therapy, further development is warranted. Disclosures M. Hackel, IHMA, Inc.: Employee, Salary. VenatoRx: Consultant, Consulting fee. D. Sahm, IHMA, Inc.: Employee, Salary. VenatoRx: Consultant, Consulting fee.

scholarly journals Management of newly diagnosed immune thrombocytopenia: can we change outcomes?

2017 ◽  
Vol 1 (24) ◽  
pp. 2295-2301 ◽  
Author(s):  
Cindy E. Neunert
Keyword(s):  
Platelet Count ◽  
Immune Thrombocytopenia ◽  
Newly Diagnosed ◽  
First Line ◽  
Current Standard ◽  
First Line Therapy ◽  
Line Therapy ◽  
Remission Rates ◽  
Treatment Naïve ◽  
Treatment Paradigm

Abstract Immune thrombocytopenia resulting from antibody-mediated platelet destruction combined with impaired platelet production is a common cause of thrombocytopenia. The decision to treat newly diagnosed patients is based on several factors including ceasing hemorrhagic manifestations, increasing the platelet count, prevention of bleeding, and inducing remission. Current standard first-line therapy is a course of corticosteroids. Although this treatment paradigm increases the platelet count in the majority of patients, a high percentage relapse after discontinuation of corticosteroid therapy. For this reason, intensification of first-line therapy that results in superior long-term remission rates would be desirable. This manuscript focuses primarily on adults with idiopathic thrombocytopenic purpura (ITP), highlighting pediatric data and practice when applicable. The primary aim is to outline upfront strategies for treatment-naive patients with ITP to enhance remission rates, taking into account assessment of the risks and benefits of these approaches.

scholarly journals Treatment-naive CLL: lessons from phase 2 and phase 3 clinical trials

Blood ◽  
2019 ◽  
Vol 134 (21) ◽  
pp. 1796-1801 ◽  
Author(s):  
Jennifer A. Woyach
Keyword(s):  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
First Line ◽  
Phase 3 ◽  
Comprehensive Review ◽  
First Line Therapy ◽  
Line Therapy ◽  
Treatment Naïve

This article provides a comprehensive review of the first-line therapy in the rapidly evolving field of chronic lymphocytic leukemia (CLL).

In vitro antifungal combination of terbinafine with itraconazole against isolates of Trichophyton spp.

2021 ◽  
Author(s):  
Anne-Laure Bidaud ◽  
Patrick Schwarz ◽  
Anuradha Chowdhary ◽  
Eric Dannaoui
Keyword(s):  
Concentration Index ◽  
Susceptibility Testing ◽  
Inhibitory Concentration ◽  
Antifungal Susceptibility ◽  
First Line ◽  
Fractional Inhibitory Concentration Index ◽  
Synergistic Interactions ◽  
First Line Therapy ◽  
Line Therapy

Terbinafine is used as first-line therapy for dermatophytosis, but the incidence of terbinafine-resistance is increasing. Combination of terbinafine with itraconazole was tested by checkerboard based on the EUCAST methodology for antifungal susceptibility testing against 9 terbinafine-susceptible and 7 terbinafine-resistant clinical isolates of Trichophyton spp. from India. Synergistic interactions were observed for 4/9 of the susceptible isolates with fractional inhibitory concentration index (FICI) values of 0.3125 to 0.5 and for 4/7 of the resistant isolates with FICI values of 0.032 to 0.3125.

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