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 (T20) is a peptide-based fusion inhibitor derived from the heptad repeat 2 (HR2) region of HIV-1 glycoprotein 41 (gp41). The inhibitor binds to the gp41 heptad repeat 1 (HR1) region, thereby blocking viral HR1/HR2 association. Mutations in HR1 have been reported to cause enfuvirtide resistance and reduce viral fitness. In this study, we first showed that scores obtained by a residue-specific all-atom probability discriminatory function (RAPDF) may be used as a reliable predictor of structural stability of gp41 mutants by comparing it to experimentally determined melting temperatures, and as a reliable indicator of enfuvirtide resistance by comparing it to experimentally determined fusion inhibition and viral fitness levels. We then generated an initial set of 28 theoretical structures of the HR1/HR2 hairpin complex where each structure consists of one mutation on HR1 known to cause enfuvirtide resistance and a wild-type amino acid at the corresponding HR2 residue. Mutations were then introduced in the corresponding HR2 residue of each structure where the wild-type amino acid was changed to each of the other nineteen amino acids. The enfuvirtide-resistant HR1 mutants with compensatory mutations at the corresponding HR2 residues had better RAPDF scores than those HR1 mutants with wild-type HR2. This indicates that mutations in HR2 improve structural stability of the HR1/HR2 hairpin complex and may lead to enhanced enfuvirtide resistance when present with resistant HR1 mutations. Modification of the amino acid side chains that contribute to enfuvirtide resistance using the RAPDF scores as a guide may help design of a second generation of fusion inhibitors against the enfuvirtide-resistant strains.
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PMID:Heptad-repeat-2 mutations enhance the stability of the enfuvirtide-resistant HIV-1 gp41 hairpin structure. 1643 Jan 94

Enfuvirtide or T-20 is the first drug approved by the FDA and the EMEA within the group of fusion inhibitors. Its mechanism of action is based on the blockade of the entry of the HIV to the body cells. Enfuvirtide is recommended in combination with other antiretroviral drugs for the treatment of patients infected by HIV that have developed resistance or intolerance to other prior antiretroviral therapies. Clinical trials have shown the effectiveness and safety of the treatment with this drug. Side effects most commonly reported are local reactions in the injection site. Enfuvirtide contributes to increase the therapeutic arsenal available for the management of the HIV infection, providing rescue therapy for patients in which prior treatments have failed.
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PMID:[Enfuvirtide: first drug of a new family of antiretroviral agents]. 1643 70

Enfuvirtide is the first of a new class of antiretrovirals know as fusion inhibitors approved for the treatment of HIV infection. It is administered via a subcutaneous injection. The patient is responsible for reconstitution from a powder and self-injection. Nurses caring for patients using enfuvirtide need a solid knowledge base about enfuvirtide administration and side effects in order to effectively educate and manage patients taking enfuvirtide. Enfuvirtide's safety and efficacy reported from phase III trials are summarized. Nursing guidelines were developed by the Association of Nurses in AIDS Care Expert Panel on Enfuvirtide. The guidelines, including suggestions on assessment, education, and management of side effects are reviewed. Teaching tools and resources are offered to assist in patient management. In addition, suggestions for proper syringe disposal and traveling with enfuvirtide are offered.
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PMID:Enfuvirtide nursing guidelines: a report from the Association of Nurses in AIDS Care Expert Panel on Enfuvirtide. 1643 21

Enfuvirtide (ENF) is the first of a new class of antiretrovirals (ARVs) known as the HIV fusion inhibitors. Two phase III studies of ENF, TORO 1 and TORO 2, demonstrated that ENF given in combination with optimized background (OB) therapy significantly improved virological response, increased the time to virological failure, and increased CD4-cell count compared with OB alone among highly treatment-experienced patients. The present study investigated the long-term clinical outcomes, costs, and cost-effectiveness of ENF. Outcomes, costs, and cost-effectiveness were estimated using a Markov model. Viral suppression and immune reconstitution were determined from the outcomes of the clinical trials. Time to immunological failure, time to AIDS-defining event (ADE), and time to death were estimated based on published mathematical models of disease progression. Costs were based on published estimates of the use and costs of ARVs, cost of managing ADEs, and cost of laboratory and other outpatient services. Cost-effectiveness was calculated as the incremental cost per year of life gained, adjusted for quality of life. The combined effects of an increase in CD4 count and delayed time to virological and immunological failure with ENF + OB were predicted to produce a mean life expectancy of 7.4 years from initiation of therapy, which was 1.8 years (1.5 quality-adjusted lifeyears [QALYs]) greater than the life expectancy associated with OB alone. The incremental cost-effectiveness of ENF + OB was estimated to be Dollars 24,604 per QALY. ENF is projected to increase time to immunological failure, delay onset of new AIDS-defining events, and increase life expectancy by more than 1.5 years among treatment-experienced HIV-infected patients. The cost-effectiveness of ENF is comparable to many existing treatment and prevention management strategies for HIV.
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PMID:Cost-effectiveness of enfuvirtide in HIV therapy for treatment-experienced patients in the United States. 1654 10

Enfuvirtide (T-20) is the first entry inhibitor approved for treatment of HIV infection and acts by inhibiting conformational changes in the viral envelope protein gp41 that are necessary for fusion of the virus and host cell membranes. Here we present genotypic and phenotypic data on viral envelopes obtained at baseline (n = 627) and after 48 weeks of enfuvirtide treatment (n = 302) from patients in the TORO (T-20 versus Optimized Regimen Only)-1 and -2 phase III pivotal studies. The amino acid sequence at residues 36-45 of gp41 was highly conserved at baseline except for polymorphism of approximately 16% at position 42. Substitutions within gp41 residues 36-45 on treatment were observed in virus from 92.7% of patients who met protocol defined virological failure criteria and occurred in nearly all cases (98.8%) when decreases in susceptibility to enfuvirtide from baseline of greater than 4-fold were observed. Consistent with previous observations, a wide range of baseline susceptibilities (spanning 3 logs) was observed; however, lower in vitro baseline susceptibility was not significantly associated with a decreased virological response in vivo. Virological response was also independent of baseline coreceptor tropism and viral subtype.
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PMID:Characterization of envelope glycoprotein gp41 genotype and phenotypic susceptibility to enfuvirtide at baseline and on treatment in the phase III clinical trials TORO-1 and TORO-2. 1670 13

The role of the fusion inhibitor enfuvirtide in nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens was assessed in an open-label study of fifty-nine highly antiretroviral drug exposed HIV-1-infected individuals. There was a reduction in plasma HIV-1 RNA of 1.43 (95% confidence interval [Cl]: -2.06, -1.22) log10 copies/ml plasma over 96 weeks, and 44% (95% CI: 31, 58) of individuals had a viral load less than 400 copies/ml. A viral load below detection at 96 weeks was predicted by a baseline genotypic sensitivity score greater than 1. There was an average increase of 67 cells/microl (95% Cl: 15, 120) from baseline CD4+ T-cell count to week 96, and the percentage of patients with CD4+ T-cell counts above 100 and 200 cells/microl increased over the trial. Injection site reactions (ISRs) were less common in people with CD4+ T-cell counts >250 cells/microl at any time during follow-up, and were more severe in patients with lower baseline peripheral fat. Adherence over 48 weeks to enfuvirtide injections ranged from 96.3-99.5%. During the 96 week trial there were two discontinuations due to ISRs and two discontinuations following hypersensitivity reactions. Over the 96 weeks of study lean body mass increased by an average 2.7 kg (95% Cl; 1.7, 3.6 kg). Mean peripheral fat increased by 0.2 kg (95% Cl; -0.2, 0.6 kg). Baseline NRTI-associated toxicities resolved in 17% of participants during follow-up. Enfuvirtide is an important component of antiretroviral therapy in highly treatment-experienced individuals where NRTI sparing may be desirable.
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PMID:Enfuvirtide in HIV-1-infected individuals changing therapy to a nucleoside reverse transcriptase inhibitor sparing regimen: the ALLIANCE Study. 1685 14

Enfuvirtide (Fuzeon, Roche), is the first member of a novel class of antiretroviral agents, the so-called fusion inhibitors, which act against HIV with a completely novel (extra cellular) mechanism of action, and can therefore be easily added to all anti-HIV association therapies including all other antiretroviral agents belonging to nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, since no interactions of any type are expected with enfuvirtide. Despite the need of a twice-daily parenteral (subcutaneous) delivery due to the polypeptide structure of the drug, and its proportionally short elimination lifetime, two extensive multicentre randomized clinical trials and a huge amount of other clinical and laboratory experiences confirmed the elevated potency and the safety profile of enfuvirtide in appropriate samples of HIV-infected patients (both adults and children), who failed and/or became intolerant to all previously available anti-HIV regimens, and had a very restricted choice of antiviral compounds showing residual activity. As a consequence, enfuvirtide is recommended as an adjunct to an "optimized background" containing at least one or two antiretroviral drugs, which are still active against the isolated viral strain, as assessed by resistance testing. The extremely promising profile of this novel anti-HIV drug and the reduced potential for the development of viral resistance (with no possibility of cross-resistance with the other anti-HIV classes) however warrant further pharmacokinetic, pharmacodynamic, pharmacogenomic, and pharmacoeconomic investigation. Also more extensive and prolonged clinical and quality of life studies are strongly needed to establish the best positioning of enfuvirtide in the current therapeutic guidelines of HIV disease and its future role, besides its current approval for salvage therapy of adult and pediatric HIV-infected patients with limited therapeutic options.
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PMID:A novel antiretroviral class (fusion inhibitors) in the management of HIV infection. Present features and future perspectives of enfuvirtide (T-20). 1691 61

Enfuvirtide is a virologically and immunologically active, injectable antiretroviral fusion inhibitor developed for the treatment of HIV infection. Patients have shown high adherence rates related to self-preparation (reconstitution) and self-administration of enfuvirtide. This review discusses the efficacy and acceptability of enfuvirtide and offers advice to help health care professionals and patients address concerns about self-injection. Practical interventions that can help minimize and manage the impact of injection-site reactions are described, including the use of a needle-free device for administering the drug.
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PMID:Enfuvirtide: patient acceptance and strategies for managing injection-site reactions. 1702 66

(1) Despite the availability of multidrug antiretroviral therapies, about 3% to 4% of HIV-infected patients exhaust nearly all available treatment options. (2) Tipranavir, an HIV protease inhibitor, is marketed in France for patients with multidrug resistance. (3) Two randomised unblinded trials are currently comparing the tipranavir + ritonavir combination with other protease inhibitors as adjuncts to optimised antiretroviral treatment in 1159 patients selected on the basis of laboratory criteria. Interim results at 48 weeks show that significantly more patients have an undetectable viral load with tipranavir + ritonavir than with other protease inhibitors (22.8% versus 10.2%). Enfuvirtide co-administration seems to reinforce the effect of tipranavir + ritonavir. In contrast, tipranavir does not seem to be more effective than other HIV protease inhibitors to which a given patient's viral population remains sensitive. (4) Tipranavir seems to be associated with higher risks of hepatic disorders, hypertriglyceridaemia, hypercholesterolaemia, and potentially severe bleeding than other protease inhibitors. (5) Tipranavir inhibits the activity of most cytochrome P450 isoenzymes. This creates a strong potential for drug interactions, but clinical experience is limited. (6) Patients on tipranavir must take 2 capsules twice a day. (7) In practice, tipranavir should be saved as a last-resort HIV protease inhibitor.
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PMID:Tipranavir: new drug. HIV protease inhibitor. A last resort. 1716 25

Enfuvirtide (ENF) is the first HIV-1 entry inhibitor used in clinical practice and is currently administered via the subcutaneous route. We here evaluated whether ENF administration leads to a change in humoral parameters, including IgE, possibly related to ENF-associated injection site reactions (ISRs). A 24-week prospective study was conducted in multidrug resistant patients enrolled in the ENF Early Access Program characterized by CD4 counts < or =100 cells/microlitre and no other active antiretroviral drug. Licensed commercial laboratory assays were used to measure the parameters considered in this study. Results are reported as medians (interquartiles IQR). Statistical analyses were performed using Wilcoxon sign rank, Wilcoxon rank sum and Kruskall Wallis tests. Total IgM, IgA and IgG did not change significantly throughout the study. Conversely, a significant increase in IgE was observed in all patients, in those with normal as well as in those with altered IgE at baseline (BL). ISRs such as induration and number of nodules were more frequent in patients with altered BL IgE. IgE increased significantly in all patients, regardless of the different stratifications in their BL CD4 counts. Of note, the ENF-induced increase in CD4 occurred significantly in all patients, independently of their BL IgE levels. The immunological response associated with ENF treatment is accompanied by a selective increase in IgE levels. Determination of IgE could be used in the monitoring ISRs associated with ENE
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PMID:Selective increase in serum IgE following enfuvirtide administration in HIV-1 infected multidrug resistant patients. 1720 Oct 88


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