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)

Enfuvirtide is the prototype member of a new class of anti HIV-1 agents, the fusion inhibitors (FI). In recent clinical trials, the compound has shown its efficacy in combination with other antiretroviral agents in vivo. However mutant strains resistant to the action of the drug arise quite rapidly in vitro and in vivo. To analyze the process of selection and evolution of HIV-1 strains resistant to enfuvirtide in vivo and to evaluate the impact of resistance on viral fitness, 12 HIV-1 infected subjects treated with T20 (enfuvirtide) for at least one year were included in the study. Gp41-coding sequences were amplified from plasma samples of these subjects at baseline and at different time points during treatment. Seven of the 12 subjects showed selection of gp41 mutations under the selective pressure of enfuvirtide. In particular, these mutations clustered in two distinct regions: (i) a mutational hot-spot localized, as previously described, in the first residues of the N-HR domain, with position number 38 as the most heavily mutated, but including also a G36V, a N42D/T, a N43D, a L44M and a L45M; (ii) other mutations were localized further downstream, within N-HR/C-HR junction and in the C-HR. A recombinant assay specifically designed for the determination of HIV-1 phenotype to FI was developed and validated. Using this assay, we observed that all of the 7 mutated clones displayed substantially reduced susceptibility to T20, IC50 ranging from 0.6 to12.8 microg/ml (>100 fold change). The residues whose mutation was associated with a potent reduction in susceptibility were V38, N42, and N43, other positions such as G36, N44 and L45 playing a minor role. None of the mutant HIV isolates showed cross-resistance to T-1249. By the same method, the HIV-1 replicative capacity of the recombinant clones was tested in the absence of drugs, and for each subject, pre-therapy clones were compared to post-therapy ones. In 3/7 subjects a significant decrease in replicative capacity of the recombinant clones was observed. The phenotypic data from this study suggest that the secondary additional mutations, could be associated with improved resistance or recovery of replicative capacity (compensatory mutations).
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PMID:Resistance and replicative capacity of HIV-1 strains selected in vivo by long-term enfuvirtide treatment. 1564 65

Enfuvirtide, the first fusion inhibitor approved for the treatment of HIV-1 infection, is a synthetic peptide that binds to HIV-1 glycoprotein 41, blocking the fusion of viral and cellular membranes. When administered subcutaneously at the recommended dose of 90 mg twice daily with optimised background antiretroviral therapy, enfuvirtide significantly reduces plasma HIV-1 RNA levels up to 48 weeks compared with optimised background therapy alone. Enfuvirtide exhibits a small volume of distribution (5.48 L), low systemic clearance (1.4 L/h) and high plasma protein binding (92%). Less than 17% of enfuvirtide is converted to a minimally active deaminated form of the parent drug. Both enfuvirtide and its metabolite are primarily eliminated via catabolism to amino acid residues. Following subcutaneous administration, enfuvirtide is almost completely absorbed, and exposure increases almost linearly with dose over the range 45-180 mg. When administered at the recommended dose in adults, subcutaneous absorption is slow and protracted, resulting in relatively flat steady-state plasma concentration-time profiles. Bioavailability is high (84.3%) and the elimination half-life (3.8 hours) supports twice-daily administration. Comparable absorption was observed from three different anatomical injection sites. The pharmacokinetic-pharmacodynamic relationship indicates that the recommended dose, in combination with other active antiretrovirals, is optimal. Enfuvirtide clearance is influenced to a small extent by sex and bodyweight but this does not necessitate dosage adjustment. In vitro and in vivo studies indicate that enfuvirtide has a low potential to interact with concomitantly administered drugs. Enfuvirtide did not influence concentrations of drugs metabolised by cytochrome P450 (CYP) 3A4, CYP2D6 or N-acetyltransferase, and had only minimal effects on those metabolised by CYP1A2, CYP2E1 or CYP2C19. Coadministration of ritonavir, ritonavir-boosted saquinavir or rifampicin (rifampin) did not result in clinically significant changes in enfuvirtide pharmacokinetics. In HIV-1-infected paediatric patients, subcutaneous dosages based on bodyweight (2 mg/kg twice daily) produce pharmacokinetics broadly similar to those observed in adults administered 90 mg twice daily.
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PMID:Pharmacokinetics, pharmacodynamics and drug interaction potential of enfuvirtide. 1565 96

The Food and Drug Administration (FDA) approved a new type of drug to treat advanced HIV-1 infection in adults and children six and older. The drug is called Fuzeon and it's the first of the so-called 'fusion inhibitor' drugs to be approved anywhere in the world. Fusion inhibitors work by inhibiting the fusion of viral and target cellular membranes, thus blocking the HIV ability to infect cells. Fuzeon's generic name is efuvirtide and it will be distributed by Roche Pharmaceuticals and Trimeris. Fuzeon is the first new class of AIDS treatment approved by the FDA in seven years. But Fuzeon will be expensive, maker sets a price of 20,000 US dollars a year, topping experts' estimated of 10,000 US dollars to 15,000 US dollars. In addition, the medication will come with a warning, its label will advise doctors to carefully monitor patients for signs of pneumonia. During the trial, more patients using Fuzeon can also cause severe allergic reactions, and skin reactions at the injection site occurred in almost all patients. Co-developed by Roche and Trimeris, a biopharmaceutical company, Fuzeon is expected to provide new hope to AIDS patients who have developed a resistance to existing medications.
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PMID:[Fuzeon, first of the so-called "fusion inhibitor" drug in new class of AIDS treatments and its warnings]. 1567 39

Enfuvirtide is a 36 amino-acid synthetic peptide derived from the HR2 sequence of the HIV-1 gp41. Enfuvirtide is different from other antiretroviral drugs by its extra-cellular action where it binds to the HR1 domain at the viral surface of the gp41. The drug inhibits the conformational change of the glycoprotein, preventing the intimate fusion between the HIV envelope and the CD4 cell membrane and finally the penetration of the viral capside into the target cells. Following a 90 mg subcutaneous injection, the plasma concentration rises rapidly to reach a 4.59 +/- 1.5 microg/ml Cmax between 5 and 7 hours. Residual concentrations are between 2.6 and 3.4 microg/ml and the bioavailability of the drug is approximately 80%. Plasma concentrations and area under curve are dose-dependant. The site of injection does not influence the pharmacokinetic parameters of the drug. Infuvirtide is not an inhibitor of the P450 cytochrome and no pharmacokinetic interactions have been reported with P450 metabolised drugs.
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PMID:[Enfuvirtide, first fusion inhibitor in the treatment of human immunodeficiency virus infection: mechanism of action and pharmacokinetics]. 1574 49

Highly active antiretroviral therapy, a combination of antiretrovirals to treat HIV-infected individuals, may fail for a number of reasons, including the selection of genetic mutations which confer resistance to the antiretroviral drugs, and poor adherence or treatment discontinuation resulting from drug toxicity. Treatment-experienced patients, who have failed therapy owing to the emergence of drug-resistant virus, have a significant unmet medical need. Enfuvirtide (T-20), the first of a new class of antiretroviral agents known as HIV fusion inhibitors, has a unique mechanism of action involving disruption of HIV entry at the stage of membrane fusion. The potent antiviral activity and favourable safety and tolerability profile of enfuvirtide has been demonstrated in combination with other agents. Its novel mechanism of action offers a low potential for cross-resistance with conventional classes of antiretrovirals, and its extracellular distribution means that drug interactions and intracellular metabolic disturbances are unlikely. Targeting viral fusion or entry will hopefully provide respite for patients who have limited treatment options following the emergence of multi-drug resistance.
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PMID:Enfuvirtide: the first HIV fusion inhibitor. 1579 36

Enfuvirtide (Fuzeon), a fusion inhibitor, is indicated in combination with other antiretroviral agents in the treatment of HIV infection in treatment-experienced adults and children aged >6 years. The addition of subcutaneous enfuvirtide to an optimised antiretroviral background regimen improved the virological and immunological response in treatment-experienced HIV-infected patients in the two large, well designed TORO (T-20 vs Optimised Regimen Only) trials. Although injection-site reactions occurred almost universally in enfuvirtide recipients, they were rarely treatment-limiting. Enfuvirtide was otherwise generally well tolerated. The challenge for clinicians is in determining the appropriate timing for enfuvirtide initiation, which requires consideration of the likelihood of a better virological response with the construction of an active background regimen versus the potential for a low rate of adherence to therapy in patients in the early stages of treatment and/or disease development. Enfuvirtide is a novel antiretroviral that is effective in HIV-infected patients whose treatment options are limited by multi-class antiretroviral resistance.
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PMID:Enfuvirtide: a review of its use in the management of HIV infection. 1590 47

Recently T-20 or enfuvirtide, the first drug of a new class of antiretrovirals targeting the entry stage of the virus life cycle, has been clinically approved. Enfuvirtide is a peptide derived from the HR2 region of the transmembrane glycoprotein from the HXB2 HIV-1 subtype B prototype strain that binds to the HR1 region. Drug resistance seems to occur in the HR1 region between amino acids 36 and 45. We examined to what extent this region is conserved in 184 non-B strains from Cameroon: 132 (71.7%) CRF02-AG, 14 (7.6%) subtype A, 11 (5.9%) F2, 9 (4.8%) subtype D, 8 (4.3%) subtype G, 4 (2.1%) CRF01-AE, 4 (2.1%) CRF11-cpx, and 2 (1.1%) CRF06-cpx. Among the 184 strains studied, no amino acid mutation was found in the highly conserved three amino acid motif at codons 36-38 (GIV) that are important determinants of viral susceptibility to enfuvirtide. Other common substitutions like Q40H and N42T were also absent. The N42S polymorphism was present in 148 (80.4%) strains. Analysis of the HR2 domain, from which the peptide is derived, indicated a much greater genetic variability as compared to HR1.
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PMID:Enfuvirtide binding domain is highly conserved in non-B HIV type 1 strains from Cameroon, West Central Africa. 1592 8

New treatment modalities for HIV infection in 2005 are based on the availability of new antiretrovirals and new strategies for their use. For reverse transcriptase inhibitors, abacavir/lamivudine and tenofovir/emtricitabine combinations minimize risks of mitochondrial toxicity and are now available as a single daily tablet. New protease inhibitors (PI) are boosted by ritonavir. Some that are already available (atazanavir, fosamprenavir) have good tolerance, resistance and dosing profiles. PIs in advanced stages of development (tipranavir and TMC114) specifically target strains with resistant mutations. Entry inhibitors affecting the CCR5 co-receptor are a new promising drug class. Enfuvirtide, a fusion inhibitor administered in subcutaneous injections, significantly improves the antiretroviral and immunologic response to antiretroviral regimens in patients with previous treatment failures. For successfully treated patients, simplification and treatment interruptions are sometimes possible. For non-responders, thorough virological-pharmacological assessment is necessary, together with access to new molecules and new drug classes.
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PMID:[New antiretroviral treatment modalities]. 1602 64

Peptides from the N-heptad repeat region of the HIV gp41 protein can inhibit viral fusion, but their potency is limited by a low tendency to form a trimeric coiled-coil. Accordingly, stabilization of N peptides by fusion with the stable coiled-coil IZ yields nanomolar inhibitors [Eckert, D. M. & Kim, P. S. (2001) Proc. Natl. Acad. Sci. USA 98, 11187-11192]. Because the antiviral potency of IZN17 is limited by self-association equilibrium, we covalently stabilized the peptide by using interchain disulfide bonds. The resulting covalent trimer, (CCIZN17)3, has an extraordinary thermodynamic stability that translates into unprecedented antiviral potency: (CCIZN17)3 (i) inhibits fusion in a cell-cell fusion assay (IC50 = 260 pM); (ii) is the most potent fusion inhibitor described to date (IC50 = 40-380 pM) in a single-cycle infectivity assay against HIV(HXB2), HIV(NL4-3), and HIV(MN-1); (iii) efficiently neutralizes acute viral infection in peripheral blood mononuclear cells; and (iv) displays a broad antiviral profile, being able to neutralize 100% of a large panel of HIV isolates, including R5, X4, and R5/X4 strains. In all of these assays, the potency of N-peptide inhibitor (CCIZN17)3 was equal to or more than the C-peptide inhibitor in clinical use, DP178 (also known as Enfuvirtide and Fuzeon). More importantly, we show that the two inhibitors, which have different targets in gp41, synergize when used in combination. These features make (CCIZN17)3 an attractive lead to develop as an antiviral drug, alone or in combination with DP178, as well as a promising immunogen to elicit a fusion-blocking neutralizing antibody response.
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PMID:Covalent stabilization of coiled coils of the HIV gp41 N region yields extremely potent and broad inhibitors of viral infection. 1612 31

In the past 25 years, the worldwide AIDS epidemic has grown such that roughly 38 million people were estimated to be living with the disease worldwide at the end of 2003. The introduction of antiretroviral-based therapies, beginning in 1987, has enabled many to live with HIV as a chronic, rather than terminal, disease. However, the emergence and spread of drug-resistant strains highlights the continued need for new therapies with novel modes of action. In 2003, the FDA and EMEA approved enfuvirtide (Fuzeon), a 36 amino acid peptide derived from the natural gp41 HR2 sequence, as the first HIV fusion inhibitor. T-1249, a 39 amino acid fusion inhibitor, is active against viruses that develop resistance to enfuvirtide. The development of FIs and the processes to manufacture enfuvirtide and T-1249 on an unprecedented scale for peptide therapeutics are presented. Synthetic routes based on a combination of solid phase peptide synthesis and solution phase fragment condensation as well as the analytical controls necessary to insure a robust process are discussed.
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PMID:Development of HIV fusion inhibitors. 1613 Jan 77


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