Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study

Lataillade, Max; Lalezari, Jacob; Kozal, Michael J.; Aberg, Judith A.; Pialoux, Gilles; Cahn, Pedro; Thompson, Melanie; Molina, Jean Michel; Moreno, Santiago; Grinsztejn, Beatriz; Diaz, Ricardo Sobhie; Castagna, Antonella; Kumar, Princy; Latiff, Gulam H; Jesus, Edwin De; Wang, Marcia; Chabria, Shiven; Gartland, Margaret; Pierce, Amy; Ackerman, Peter; Llamoso, Cyril

doi:10.1016/s2352-3018(20)30240-x

Cited by 73 publications

(119 citation statements)

References 25 publications

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“…FTR, a prodrug of temsavir, is an attachment inhibitor that prevents HIV entry into the CD4 T-cell and is approved for heavily treatment-experienced adults with multi-drug-resistant HIV. FTR-related mutations have been reported at a high rate (48%) in PLHIV receiving FTR as functional monotherapy or with only one or two fully active ARVs through week 96 [107]. Regardless of this limitation, the efficacy and tolerability data support the use of FTR as a salvage treatment option in patients with multi-drug-resistant HIV.…”

Section: Novel Approaches To Combat Hiv Drug Resistancementioning

confidence: 99%

HIV Drug Resistance in Children and Adolescents: Always a Challenge?

2021

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Purpose of Review With the expanded roll-out of antiretrovirals for treatment and prevention of HIV during the last decade, the emergence of HIV drug resistance (HIVDR) has become a growing challenge. This review provides an overview of the epidemiology and trajectory of HIVDR globally with an emphasis on pediatric and adolescent populations. Recent Findings HIVDR is associated with suboptimal virologic suppression and treatment failure, leading to an increased risk of HIV transmission to uninfected people and increased morbidity and mortality among people living with HIV. High rates of HIVDR to non-nucleoside reverse transcriptase inhibitors globally are expected to decline with the introduction of the integrase strand transfer inhibitors and long-acting combination regimens, while challenge remains for HIVDR to other classes of antiretroviral drugs. Summary We highlight several solutions including increased HIV viral load monitoring, expanded HIVDR surveillance, and adopting antiretroviral regimens with a high-resistance barrier to decrease HIVDR. Implementation studies and programmatic changes are needed to determine the best approach to prevent and combat the development of HIVDR.

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Section: Novel Approaches To Combat Hiv Drug Resistancementioning

confidence: 99%

HIV Drug Resistance in Children and Adolescents: Always a Challenge?

2021

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“…[17][18][19] In a follow-up intent-to-treat analysis at week 96, overall viral suppression increased to 60%; the nonrandomized cohort viral suppression rate was 37%. 20 A subgroup analysis at 96 weeks resulted in immunological improvement across all treatment arms, with a mean CD4 increase of 205 in the randomized cohort. A higher percentage of serious adverse events was present in participants with a baseline CD4 count of <20 cells/µL (46%) compared with participants with a CD4 count of ≥200 cells/µL (27%).…”

Section: Pharmacokineticsmentioning

confidence: 93%

“…17-19 In a follow-up intent-to-treat analysis at week 96, overall viral suppression increased to 60%; the nonrandomized cohort viral suppression rate was 37%. 20…”

Section: Clinical Trialsmentioning

confidence: 99%

“…The authors attributed the 29 deaths to complications of advanced disease and infection. 20 After FTR is converted to TMR, the primary process of metabolism is via esterase-mediated hydrolysis, with slight cytochrome P450 (CYP) 3A4 involvement. TMR is not a major CYP inhibitor or inducer; however, it is a P-glycoprotein (P-gp) substrate and can inhibit organic anion transporter protein (OATP) 1B1/3.…”

Section: Drug Interactions Safety Concerns and Adverse Reactionsmentioning

confidence: 99%

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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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“…Understanding the basic mechanisms by which HIV particles are replicated in host cells is immensely important in the context of fundamental research underpinning new antiviral drug development, especially when there is still no early prospect of an HIV vaccine. Current antiretroviral drugs come in eight classes (protease inhibitors, integrase inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, chemokine receptor antagonists, attachment inhibitors, and post attachment inhibitors) [1][2][3]. These are used in combination in current clinical practice to minimize exerting selection pressure on the viral populations inside patients.…”

Section: Introductionmentioning

confidence: 99%

Visualizing HIV-1 Capsid and Its Interactions with Antivirals and Host Factors

Wilbourne

Zhang

2021

Viruses

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Understanding of the construction and function of the HIV capsid has advanced considerably in the last decade. This is due in large part to the development of more sophisticated structural techniques, particularly cryo-electron microscopy (cryoEM) and cryo-electron tomography (cryoET). The capsid is known to be a pleomorphic fullerene cone comprised of capsid protein monomers arranged into 200–250 hexamers and 12 pentamers. The latter of these induce high curvature necessary to close the cone at both ends. CryoEM/cryoET, NMR, and X-ray crystallography have collectively described these interactions to atomic or near-atomic resolutions. Further, these techniques have helped to clarify the role the HIV capsid plays in several parts of the viral life cycle, from reverse transcription to nuclear entry and integration into the host chromosome. This includes visualizing the capsid bound to host factors. Multiple proteins have been shown to interact with the capsid. Cyclophilin A, nucleoporins, and CPSF6 promote viral infectivity, while MxB and Trim5α diminish the viral infectivity. Finally, structural insights into the intra- and intermolecular interactions that govern capsid function have enabled development of small molecules, peptides, and truncated proteins to disrupt or stabilize the capsid to inhibit HIV replication. The most promising of these, GS6207, is now in clinical trial.

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Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study

Cited by 73 publications

References 25 publications

HIV Drug Resistance in Children and Adolescents: Always a Challenge?

HIV Drug Resistance in Children and Adolescents: Always a Challenge?

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

Visualizing HIV-1 Capsid and Its Interactions with Antivirals and Host Factors

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