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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enfuvirtide (T-20) is a novel antiretroviral agent that blocks HIV-1 cell fusion. A 28-day randomized dose-comparison study was conducted to determine the safety, pharmacokinetics, and antiviral activity of enfuvirtide in 78 HIV-infected adults, most with extensive treatment experience. Patients received enfuvirtide, added to a failing regimen, either by continuous subcutaneous infusion (CSI: 12.5, 25, 50 or 100 mg/day) or by subcutaneous (SC) injection (50 or 100 mg twice daily). Dose-related decreases in viral load were observed, with a maximum mean reduction from baseline of 1.6 log(10) copies/ml (p< 0.001) seen in the 100 mg bid SC group. Most responses diminished by 28 days. Plasma pharmacokinetics and antiviral responses were more consistent for SC injection than for CSI because of technical difficulties experienced with CSI. Injection site reactions were common but generally mild. These results indicate that enfuvirtide is a promising new therapeutic agent for HIV-infected patients, including those with prior antiretroviral treatment.
AIDS Res Hum Retroviruses 2002 Jul 01
PMID:The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. 1216 74

Despite the success of combination HAART in improving the clinical prognosis of HIV-infected patients, therapeutic options are limited for many patients, particularly those with extensive treatment experience. Resistance, cross-resistance, and toxicity combine to threaten the durability of antiviral response, necessitating the development of novel agents. The HIV life cycle has many potential targets for inhibition in addition to the current reverse transcriptase and protease targets. These include the HIV integrase, nucleocapsid, and Tat proteins and the viral entry process. Entry inhibitors can be classified as attachment, coreceptor, and fusion inhibitors, according to the stage in the entry process at which they act. Most advanced in development of these is the fusion inhibitor enfuvirtide. Enfuvirtide is a potent inhibitor of HIV fusion whose novel mechanism of action and extracellular nature mean that it will induce limited cross-resistance to currently approved antiretrovirals and fewer toxicities.
AIDS Read 2003 Mar
PMID:New classes of HIV drugs on the horizon. A review of the presentation at the satellite symposium "New hope: advancing care in HIV infection" at the 15th annual Association of Nurses in AIDS Care conference, November 2002. 1276 59

Proof of the concept that a fusion inhibitor could mediate clinically significant antiviral responses came from the demonstration that patients receiving 100 mg of enfuvirtide daily as monotherapy for 14 days achieved a mean reduction in viral load of 1.5 log10 copies/mL. Phase 2 studies established subcutaneous injection of 100 mg of enfuvirtide twice daily as the dosage of choice. In pivotal phase 3 trials, enfuvirtide was added to an optimized background regimen in heavily treatment-experienced patients. Virologic and immunologic responses were significantly better in patients receiving enfuvirtide in addition to optimized background regimens than in those receiving optimized background alone, with the incremental reduction in viral load between arms being 0.934 log10 copies/mL after 24 weeks of therapy. Subgroup analyses demonstrated this benefit to be similar regardless of age, sex, race, and baseline viral load. Enfuvirtide was well tolerated, with injection site reactions being the most common adverse event, although they were rarely treatment-limiting.
AIDS Read 2003 Mar
PMID:Clinical safety and efficacy of enfuvirtide (T-20), a new fusion inhibitor. A review of the presentation at the satellite symposium "New hope: advancing care in HIV infection" at the 15th annual Association of Nurses in AIDS Care conference, November 2002. 1276 60

The parenteral route of enfuvirtide administration requires that patients become familiar with reconstituting and administering the agent and in managing injection site reactions (ISRs). Since the majority of patients will experience at least one ISR, minimizing this effect is important, and several techniques can be taught to help alleviate the onset and symptoms of ISRs. Enfuvirtide patients usually encounter little difficulty with administration, and most report little impact of self-injections on their daily lives. However, instruction by nurses is crucial in training patients to administer enfuvirtide and to build this routine into their daily lives, thereby furthering the acceptance of enfuvirtide and promoting compliance. Patient education tools will provide clear and informative support, together with practical solutions to incorporate enfuvirtide therapy into daily life and travel. Easy access to the nurse and physician, coupled with an effective nurse-patient relationship, will be key in supporting good compliance with enfuvirtide therapy.
AIDS Read 2003 Mar
PMID:Treatment with a new fusion inhibitor: patient issues with enfuvirtide (T-20). A review of the presentation at the satellite symposium "New hope: advancing care in HIV infection" at the 15th annual Association of Nurses in AIDS Care conference, November 2002. 1276 61

The replicative cycle of the human immunodeficiency virus (HIV) can be interrupted at several stages. Until recently only the viral reverse transcriptase and protease were the only enzymes targeted by antiretroviral agents. However, the first HIV entry inhibitor (T-20, Enfuvirtide, Fuseon) to be used in humans has been approved by the Food and Drug Administration (FDA). The HIV entry process is considered as an attractive target for chemotherapeutic intervention, as blocking HIV entry into its target cell leads to suppression of viral infectivity, replication and the cytotoxicity induced by virus-cell contacts. HIV-1 entry into target cells is a multistep process: virus attachment is initiated by the binding of trimeric envelope glycoprotein gp120 complexes on the virions to glycosylated T-cell surface receptor (CD4) and HIV GPCR coreceptors (CCR5 or CXCR4) leading to envelope glycoprotein gp41-dependent fusion-pore formation and membrane fusion. A number of compounds are being developed to specifically target each of these steps leading to virus entry and some compounds have reached early clinical development. Conversely, agents such as the CCR5 antagonist Tak-779 and the CXCR4 antagonist AMD3100 are not longer being thought as relevant anti-HIV agents but have given way to new analogues with improved properties. This review summarizes the current state of HIV entry inhibitors, their mechanisms of action and their therapeutic value against HIV infection and AIDS.
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PMID:Virus entry as a target for anti-HIV intervention. 1287 Nov 11

The development of highly active antiretroviral therapy has improved life expectancy and reduced progression to acquired immunodeficiency syndrome in human immunodeficiency virus (HIV)-infected patients. However, resistance to currently available classes of antiretroviral drugs has become a problem, limiting the options for patients with advanced disease who have been heavily treated. Enfuvirtide (T-20; ENF), a synthetic peptide, is the first of a new class of antiretrovirals that block entry of virus into host cells. ENF interferes with conformational changes required for membrane fusion and injection of virus into the host cell. Optimal treatment of HIV infection will likely require combinations of drugs that target novel stages of HIV type 1 entry and replication.
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PMID:Enfuvirtide (T-20): a novel human immunodeficiency virus type 1 fusion inhibitor. 1452 75

Human immunodeficiency virus (HIV) is a retrovirus that is the causative agent of acquired immunodeficiency syndrome (AIDS). Current HIV therapy is based on targeting two critical enzymes in the viral replication machinery: reverse transcriptase and a virally encoded protease. Although mortality rates due to HIV infection have been dramatically reduced, AIDS remains a major health problem throughout the world. The emergence of HIV variants that are resistant to current therapies and potential toxicity associated with their chronic use has highlighted the need for new approaches to HIV inhibition. Identification of the mechanisms underlying viral entry into the host cell has provided a number of novel therapeutic targets and the first of these HIV fusion inhibitors (enfuvirtide [pentafuside, T-20, Fuzeon; Roche Laboratories and Trimeris]) has recently been approved in the US and Europe. This review will focus on recent progress in the development of therapeutics that target the HIV entry process.
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PMID:HIV entry and fusion inhibitors. 1515 32

The introduction of enfuvirtide (FUZEON) represents an important advance in the treatment of therapy-experienced patients with HIV-1 infection. However, parenteral self-administration, and the advanced disease and antiretroviral experience of patients currently most needing enfuvirtide introduce unique usage considerations. Enfuvirtide has been shown to provide clinically relevant improvements in CD4 cell counts and reductions in HIV viraemia across all subgroups of treatment-experienced patients studied, including those taking few or no other active drugs. However, optimal outcome results from initiation when the CD4 cell count is above 100 x 10(6) cells/l and viraemia below 1 x 10(5) copies/ml, as part of a newly constructed third or fourth antiretroviral regimen in combination with one or two other antiretrovirals to which the virus remains sensitive. Resistance testing should be used where available to guide background drug selection. Where insufficient options for an effective background exist, enfuvirtide should still be considered and treatment undertaken with the aim of achieving an immunological or clinical response, despite the unlikelihood of a sustained virological outcome. Similarly, where there is no viable alternative treatment, enfuvirtide should be continued following virological failure wherever ongoing immunological or clinical benefit is discerned. Injection site reactions (ISRs) are common on enfuvirtide and will affect almost all patients. ISRs are manageable and seldom activity- or treatment-limiting. Bacterial pneumonia and systemic hypersensitivity reactions have also been reported uncommonly. A structured series of patient visits with a healthcare professional provides an atmosphere of ongoing training and support that may prevent 'injection fatigue', maintain adherence and minimise the incidence of ISRs. An initial investment in establishing such procedures can be expected to yield significant returns in patient confidence and benefit on enfuvirtide.
AIDS 2004 May 21
PMID:Clinical management of treatment-experienced, HIV-infected patients with the fusion inhibitor enfuvirtide: consensus recommendations. 1516 29

The gp41 subunit of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein plays an important role in HIV-1 entry and severs as an attractive target for development of HIV-1 entry inhibitors, a new class of anti-HIV drugs. Triggered by gp120 binding to CD4 and a coreceptor, gp41 undergoes a conformation shift from a native prefusogenic state to a fusogenic state, in which the N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR) associate to form a six-helix bundle, representing the fusion-active gp41 core. Any compound that disrupts the gp41 six-helix bundle formation may inhibit the gp41-mediated membrane fusion, thereby blocking HIV-1 entry into target cells. Peptides derived from the gp41 NHR and CHR regions, designated N- and C-peptides, can interact with the counterpart regions in gp41 and interfere with the six-helix bundle formation between the viral NHR and CHR region, thus inhibiting fusion of the virus with the target cell. One of the C-peptides, T-20 (brand name: Fuzeon), was recently approved by the US FDA as the first HIV entry inhibitor which can be used for treatment of AIDS patients who fail to respond to the current antiretroviral drugs, e.g., the reverse transcriptase inhibitors and protease inhibitors. The limitations of T-20 include lack of oral availability and high cost of production. Thus it is essential to develop small molecule HIV-1 entry inhibitors targeting gp41. This review summarizes the newly developed techniques for high throughput screening (HTS) and characterization of the HIV-1 entry inhibitors targeting gp41. The theories behind these techniques are also discussed. It is expected that the "drug-like" compounds with potent HIV-1 fusion inhibitory activity will be identified in the near future and used as leads for development of the low molecular weight HIV-1 entry inhibitors for the chemotherapy of HIV-1 infection and AIDS.
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PMID:High throughput screening and characterization of HIV-1 entry inhibitors targeting gp41: theories and techniques. 1518 May 43

An increasing number of human immunodeficiency virus (HIV)-infected patients have detectable viraemia despite treatment with multiple-drug combinations or have developed resistance to all available classes of antiretroviral therapy. HIV entry has become an important pharmacological target. Enfuvirtide is the first HIV entry inhibitor to be approved for the treatment of drug-experienced patients but several other agents are progressing through preclinical and clinical trials. However, because different entry inhibitors target different parts of the entry process their combined effects could be synergistic or generate different distinct profiles of drug-resistance. The HIV envelope glycoprotein that drives HIV entry is highly variable. Its plasticity allows HIV to escape the immune system and its variability is associated with HIV tropism, fitness and replicative capacity. Thus, mutations that confer resistance to entry inhibitors will modify these parameters. Therapeutic strategies that aim at blocking virus entry may also be used to alter the natural evolution of HIV in an unprecedented way. Here, we will describe the structure and function of the envelope glycoprotein complex that constitute the basis for the emergence of resistance to HIV entry inhibitors, review those HIV entry inhibitors for which drug-resistance has been evaluated and discuss the interplay between viral resistance to inhibitors of HIV entry and the pathogenicity of HIV and AIDS.
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PMID:HIV-resistance to viral entry inhibitors. 1518 May 44


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