Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection

Kozal, Michael J.; Aberg, Judith A.; Pialoux, Gilles; Cahn, Pedro; Thompson, Melanie; Molina, Jean‐Michel; Grinsztejn, Beatriz; Diaz, Ricardo Sobhie; Castagna, Antonella; Kumar, Princy; Latiff, Gulam H; DeJesus, Edwin; Gummel, Mark; Gartland, Margaret; Pierce, Amy; Ackerman, Peter; Llamoso, Cyril; Lataillade, Max

doi:10.1056/nejmoa1902493

Cited by 131 publications

(176 citation statements)

References 17 publications

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“…Using smFRET, we have found that many broadly neutralizing antibodies (bNAbs) exhibit a preference for the state 1 conformation of the native Env trimer (10,20). Allosteric entry blockers of the Bristol-Myers Squibb (BMS) series (BMS-626529/Temsavir and BMS-378806) also stabilize HIV-1 Env in state 1 (10,20,(28)(29)(30)(31). The preference of bNAbs for state 1 suggests that Env-targeted immunogens intended to elicit such antibodies should resemble the pretriggered state 1 conformation.…”

mentioning

confidence: 99%

Shedding-Resistant HIV-1 Envelope Glycoproteins Adopt Downstream Conformations That Remain Responsive to Conformation-Preferring Ligands

Reichard

et al. 2020

J Virol

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The HIV-1 envelope glycoprotein (Env) trimer of gp120-gp41 heterodimers mediates virus entry into CD4+ cells. Single-molecule Fluorescence Resonance Energy Transfer (smFRET) has revealed that native Env on the surface of viruses predominantly exists in a pre-triggered conformation (State 1) that is preferentially recognized by many broadly neutralizing antibodies (bNAbs). Env is activated by binding receptor CD4, which drives transitions through a default intermediate conformation (State 2) into the three-CD4-bound open conformation (State 3). The application of smFRET to assess the conformational state of existing Env constructs and ligand complexes recently revealed that all current high-resolution structures correspond to downstream States 2 and 3. The structure of State 1, therefore, remains unknown. We sought to identify conditions whereby HIV-1 Env could be stabilized in the pre-triggered State 1 for possible structural characterization. Shedding of gp120, known to severely complicate structural studies, can be prevented by using the uncleaved gp160JR-FL precursor with alterations in the protease cleavage site (R508S/R511S), or by introducing a disulfide bridge between gp120 and gp41 designated “SOS” (A501C/T605C). smFRET demonstrated that both shedding-preventing modifications shifted the conformational landscape of Env downstream towards States 2 and 3. However, both membrane-bound Env proteins on the surface of intact viruses remained conformationally dynamic, responsive to state-stabilizing ligands, and able to be stabilized in State 1 by specific ligands such as the BMS entry inhibitors. The here-described identification of State 1-stabilizing conditions may enable structural characterization of the State 1 conformation of HIV-1 Env. IMPORTANCE The HIV-1 envelope glycoprotein (Env) opens in response to receptor CD4 binding from a pre-triggered (State 1) conformation through a necessary intermediate to the three-CD4-bound conformation. The application of smFRET to test the conformational state of existing Env constructs and ligand complexes used for high-resolution structures recently revealed that they correspond to the downstream conformations. The structure of the pre-triggered Env conformation, preferentially recognized by broadly neutralizing antibodies, remains unknown. Here, we identify experimental conditions that stabilize membrane-bound and shedding-resistant virus Env trimers in State 1, potentially facilitating structural characterization of this unknown conformational state.

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confidence: 99%

Shedding-Resistant HIV-1 Envelope Glycoproteins Adopt Downstream Conformations That Remain Responsive to Conformation-Preferring Ligands

Reichard

et al. 2020

J Virol

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“…The primary outcome was a mean change in log10 HIV-1 RNA from day 1 to day 8, and secondary outcomes included percentages of patients achieving an HIV-1 RNA <40 copies/mL at 24 and 48 weeks. 17,18…”

Section: Clinical Trialsmentioning

confidence: 99%

“…15,16 Phase 3 Trials BRIGHTE, a multiarm, randomized, placebo-controlled trial, investigated the safety and efficacy of FTR in heavily treatment-experienced patients (n = 371) with multidrugresistant HIV-1. 17 Participants were included if they had documented resistance, intolerability, or contraindications to ARVs in at least 3 classes. Participants additionally must have been prescribed a failing ARV regimen with a confirmed plasma HIV RNA ≥400 copies/mL and have no viable treatment regimens available.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Fostemsavir: A Novel Attachment Inhibitor for Patients With Multidrug-Resistant HIV-1 Infection

Hiryak

Koren

2020

Ann Pharmacother

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Objective To review the efficacy and safety of fostemsavir (FTR) for the treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced adults who are failing their current antiretroviral regimen. Data Sources Clinical trials and review articles were obtained through PubMed (2015 to July 2020) using the search terms fostemsavir, BMS-663068, and GSK3684934. Study Selection and Data Extraction All relevant articles, trials, and abstracts in the English language were included. Data Synthesis FTR demonstrates a novel mechanism of action, preventing virus attachment to the host CD4 receptor. FTR extended-release 600-mg tablets every 12 hours orally has proven beneficial in obtaining viral suppression for heavily treatment-experienced patients with multidrug-resistant infection refractory to other agents, as indicated in phase 3 trials. Treatment courses were evaluated to 96 weeks with significant viral load reductions noted within the first 24 weeks. Adverse events commonly reported include nausea, vomiting, diarrhea, fatigue, and headache. Serious events and fatality were not attributed to FTR and occurred because of advancement of HIV or other acute infection. Relevance to Patient Care and Clinical Practice FTR presents a new treatment option for patients with multidrug resistance and intolerability to other medications. The favorable adverse effect profile of FTR alongside the limited drug interaction profile makes it a viable option in a salvage regimen. Conclusions FTR provides an alternative agent when composing a regimen for patients with multidrug-resistant HIV-1 infection. It is generally well tolerated, with few significant interactions, and neither renal nor hepatic dose adjustments are required.

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“…51 No crossresistance to other drugs have been demonstrated invitro, including entry inhibitors. 52,52,54 ABX464-It is an investigational drug having both antiinflammatory and antiviral activity by interfering with pre mRNA splicing and have been investigated for a wide range of diseases such as HIV, Ulcerative colitis, COVID 19 and Rheumatoid arthritis etc. 55,56,57,58 A wide array of molecules have been developed for the therapy of HIV infections.…”

Section: Attachment Inhibitor-mentioning

confidence: 99%

A Concise Review of Existing Therapies and Recent Advances in the Management of HIV Infection

Lal¹,

Kumar²,

Dutta³

et al. 2020

IJPSRR

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Human immunodeficiency virus (HIV) is an RNA retrovirus capable of replicating its genome by the DNA dependent RNA polymerase (DdRp). The virus infects the lymphocytes with the help of viral glycoproteins like Gp 120 and Gp 41. The entry of virus leads to the release of viral RNA inside the host cell, which is further replicated, and assembly of virion particles leads to the release of viral particles that further infect the other host cells. Established therapies include those that inhibit the entry of virus in the host cell, those inhibiting the integrase activity, those acting as protease inhibitors and also we have Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Non-Nucleoside reverse transcriptase inhibitors (NNRTIs) with NRTIS being the competitive inhibitors of DdRp also show mitochondrial toxicity. Protease inhibitors are known for their adverse effect profile and several drug interactions due to their enzyme inhibitory property. The most effective approach in the management is the highly active antiretroviral therapy containing the combined use of drugs having varied mechanisms of action. Still, long term use of these agents can end up in resistance against these agents. Well documented adverse effect profile along with various drug interactions associated with anti-HIV drugs mandates the need for the development of newer drugs against HIV. Newer molecules provide a better safety profile and better alternatives for drug-resistant cases. Therefore, this review focuses on existing therapies along with various newer pipeline drugs with their mechanisms and advantages over the existing therapies.

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Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection

Cited by 131 publications

References 17 publications

Shedding-Resistant HIV-1 Envelope Glycoproteins Adopt Downstream Conformations That Remain Responsive to Conformation-Preferring Ligands

Shedding-Resistant HIV-1 Envelope Glycoproteins Adopt Downstream Conformations That Remain Responsive to Conformation-Preferring Ligands

Fostemsavir: A Novel Attachment Inhibitor for Patients With Multidrug-Resistant HIV-1 Infection

A Concise Review of Existing Therapies and Recent Advances in the Management of HIV Infection

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