Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Four heavily antiretroviral-experienced HIV-infected patients had significant plasma HIV-RNA reductions (>1 log) after beginning an Enfuvirtide (ENF)-based rescue regimen. However, all had viral rebound shortly thereafter, sustaining high levels of plasma viremia over 80 weeks. These patients developed rapidly genotypic and phenotypic resistance to ENF. Mutations within the HR1 env region were selected (N43D in three and G36V/D in one), resulting in high-level phenotypic resistance to ENF. Interestingly, two patients had a sustained CD4+ T-cell increase and two maintained stable CD4+ T-cell counts despite virologic failure under ENF. The possible mechanisms involved in this response were examined. Changes in virus tropism from R5 to R5/X4 were observed in two patients, in parallel with increases in ENF phenotypic resistance. Low levels of T-cell activation, T-cell turnover, and cytotoxic T lymphocyte (CTL) activity were found in all four patients. An overall increase in the proportion of viruses released from cells of the macrophage lineage was observed. In summary, single mutations at the HR1 env region result in significant loss of susceptibility to ENF. Despite virologic failure, these patients may maintain elevated CD4+ counts through a reduction in their overall immune activation.
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PMID:Evolution of genotypic and phenotypic resistance to Enfuvirtide in HIV-infected patients experiencing prolonged virologic failure. 1525 64

The 5th Antiviral Drug Discovery and Development Summit provided an up-to-date snapshot of the ongoing developments in the area. The topics covered ranged from updates on recently launched drugs (Kaletra), Fuzeon) and new investigational inhibitors (T-1249, Reverset, UK-427857, L-870810, PA-457, remofovir, VX-950), to the discovery of new antiviral targets and advances in technologies that may provide the substrate for the next generation of therapeutics. It is apparent from the range of presentations that much of today's efforts are focused on developing new classes of HIV inhibitors (gp41, integrase), while there is also considerable progress in hepatitis C, where a number of inhibitors have or should reach proof-of-concept studies in the coming months. Here we provide the highlights of this meeting, with particular emphasis on the new developments in HIV and hepatitis C virus.
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PMID:5th Antiviral Drug Discovery and Development Summit. 1526 42

This study assessed the impact of enfuvirtide on health-related quality of life (HRQoL). Patients enrolled in 2 phase 3 trials T-20 versus Optimized Regimen Only (TORO 1 and 2) completed the Medical Outcomes Study (MOS)-HIV questionnaire at baseline and at 4, 8, 16, and 24 weeks. A total of 995 treatment-experienced HIV-1-infected individuals received either self-administered enfuvirtide (90 mg twice daily) + optimized background (OB) or OB alone and had at least 1 follow-up visit. Data from the 2 clinical trials were pooled. Analysis of covariance was used to evaluate changes in the 10 MOS-HIV scale scores and 2 summary scores. Least-squares means for these changes were calculated and used to test for between-group differences. There were no significant between-group differences in any HRQoL measure at baseline. Most MOS-HIV scores showed improvement in the enfuvirtide arm compared with OB alone, although only some of these were significant. Improvements in the general health scale were significantly higher in the enfuvirtide arm compared with OB alone at all post-baseline time points. No scale or summary score for the OB arm showed a significantly greater improvement in score from baseline compared with the enfuvirtide arm, at any time point. The mental health summary score at 24 weeks was significantly higher in the enfuvirtide arm compared with OB alone. Enfuvirtide in addition to an OB regimen does not adversely affect and may improve HRQoL when self-administered for up to 24 weeks by treatment-experienced, HIV-1-infected individuals.
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PMID:Health-related quality of life with enfuvirtide (ENF; T-20) in combination with an optimized background regimen. 1531 73

One likely mechanism of virological failure is poor antiretroviral drug diffusion in sites of viral replication such as the genital tract. We measured antiretroviral drug concentrations in blood and semen in 13 HIV-infected men failing treatment. Enfuvirtide did not cross the blood-testis barrier, whereas tenofovir accumulated in semen. Unlike indinavir, semen concentrations of lopinavir, amprenavir, saquinavir and efavirenz were ineffective. These are worrying findings, because suboptimal semen drug concentrations may enhance the risk of sexually transmitted drug-resistant HIV variants.
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PMID:Penetration of enfuvirtide, tenofovir, efavirenz, and protease inhibitors in the genital tract of HIV-1-infected men. 1535 84

Four antiretroviral drugs were approved in 2003: emtricitabine (FTC, Emtriva), and nucleoside reverse transcriptase inhibitor (NRTI); the protease inhibitors (PIs) atazanavir (Reyataz) and fosamprenavir (Lexiva); and T-20 (enfuvirtide, Fuzeon), the first of a new anti-HIV drug class, entry inhibitors.
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PMID:The pipeline: three to watch. 1538 38

A recently approved peptidic human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, T-20 (Fuzeon; Trimeris Inc.), has shown significant promise in clinical application for treating HIV-1-infected individuals who have failed to respond to the currently available antiretroviral drugs. However, T-20 must be injected twice daily and is too expensive. Therefore, it is essential to develop orally available small molecule HIV-1 fusion inhibitors. By screening a chemical library consisting of "drug-like" compounds, we identified two N-substituted pyrroles, designated NB-2 and NB-64, that inhibited HIV-1 replication at a low micromolar range. The absence of the COOH group in NB-2 and NB-64 resulted in a loss of anti-HIV-1 activity, suggesting that this acid group plays an important role in mediating the antiviral activity. NB-2 and NB-64 inhibited HIV-1 fusion and entry by interfering with the gp41 six-helix bundle formation and disrupting the alpha-helical conformation. They blocked a d-peptide binding to the hydrophobic pocket on surface of the gp41 internal trimeric coiled-coil domain. Computer-aided molecular docking analysis has shown that they fit inside the hydrophobic pocket and that their COOH group interacts with a positively charged residue (K574) around the pocket to form a salt bridge. These results suggest that NB-2 and NB-64 may bind to the gp41 hydrophobic pocket through hydrophobic and ionic interactions and block the formation of the fusion-active gp41 core, thereby inhibiting HIV-1-mediated membrane fusion and virus entry. Therefore, NB-2 and NB-64 can be used as lead compounds toward designing and developing more potent small molecule HIV-1 fusion inhibitors targeting gp41.
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PMID:N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion. 1550 64

Enfuvirtide is the first of a new class of antiretroviral agents recently approved for the treatment of human immunodeficiency virus (HIV)-1 infection. Present available data suggest that enfuvirtide may be a promising agent for the control of HIV infection in patients who have previously received reverse transcriptase inhibitor and protease inhibitor regimens and who are either intolerant to such drugs and/or who have gone into virological failure. Perhaps the greater limitation to the clinical use of enfuvirtide is the cost, limiting its use in the developing world.
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PMID:Enfuvirtide: a new class of antiretroviral therapy for HIV infection. 1553 6

Enfuvirtide is a fusion inhibitor used for the treatment of HIV infection. It is an injectable drug, with the patient being responsible for reconstitution as well as injection. The authors present the results of Phase III trials with enfuvirtide. A summary of efficacy, tolerability, pharmacokinetics, resistance, and adverse events from the Phase III trials with enfuvirtide is presented. Enfuvirtide is well tolerated, and no limiting pharmacokinetic interactions have been published thus far. A review of patient perception of self-injection is also summarized. The data reviewed demonstrate that most patients find self-injection easy and do not find that it interferes with activities of daily living. Data on injection site reactions (ISRs), one of the most common adverse events of enfuvirtide, is highlighted, as is nursing management of ISRs. Finally, the authors discuss research that could help further understanding of enfuvirtide and examine some barriers clinicians may face when prescribing this medication.
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PMID:Enfuvirtide (T-20): potentials and challenges. 1553 17

In 2003 the first virus entry inhibitor, the anti-HIV peptide T20 (Fuzeon, enfuvirtide), was approved for treatment of advanced Human Immunodeficiency Virus Type 1 infection. T20 is an unconventional antiviral drug, as it does not target a viral replicase or protease but a conformational transition within the HIV1 fusion protein gp41 required for virus-cell membrane fusion. Beyond membrane fusion, numerous early drug targets have been identified that will allow for large scale screening or structure-based drug design. The first encounter of the virus with the host might be through binding to attachment receptors, such as the C-type lectins DC- and L-SIGN, which might play an important role of infection for a large number of enveloped viruses by capturing, concentrating and transmitting infectious virions. Once a virus reaches its target cell, a cascade of events generally starting with the interaction of viral envelope glycoproteins with specific entry receptors and co-receptors is necessary in order to trigger the virus-cell membrane fusion. The present review will highlight recent advances in the identification of new drugs and targets at the level of virus entry for three major human pathogens accounting for several hundred million infections worldwide: HIV, Dengue Virus and Hepatitis C virus.
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PMID:Virus attachment and entry offer numerous targets for antiviral therapy. 1557 65

Fuzeon (also known as T-20 or enfuvirtide), one of the C-peptides derived from the HIV-1 envelope glycoprotein transmembrane subunit gp41 C-terminal heptad repeat (CHR) region, is the first member of a new class of anti-HIV drugs known as HIV fusion inhibitors. It has been widely believed that T-20 shares the same mechanism of action with C34, another C-peptide. The C34 is known to compete with the CHR of gp41 to form a stable 6-helix bundle (6-HB) with the gp41 N-terminal heptad repeat (NHR) and prevent the formation of the fusogenic gp41 core between viral gp41 NHR and CHR, thereby inhibiting fusion between viral and target cell membranes. Here we present data to demonstrate that, contrary to this belief, T-20 cannot form stable 6-HB with N-peptides derived from the NHR region, nor can it inhibit the 6-HB formation of the fusogenic core. Instead, it may interact with N-peptides to form unstable or insoluble complexes. Our data suggest that T-20 has a different mechanism of action from C34. The interaction of T-20 with viral NHR region alone may not prevent the formation of the fusion active gp41 core. We also demonstrate that the T-20-mediated anti-HIV activity can be significantly abrogated by peptides derived from the membrane-spanning domain in gp41 and coreceptor binding site in gp120. These new findings imply that T-20 inhibits HIV-1 entry by targeting multiple sites in gp41 and gp120. Further elucidation of the mechanism of action of T-20 will provide new target(s) for development of novel HIV entry inhibitors.
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PMID:Different from the HIV fusion inhibitor C34, the anti-HIV drug Fuzeon (T-20) inhibits HIV-1 entry by targeting multiple sites in gp41 and gp120. 1564 Jan 62


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