enfuvirtide and Acquired-Immunodeficiency-Syndrome

We sought to project the lifetime cost of medical care for human immunodefiency virus (HIV)-infected adults using current antiretroviral therapy (ART) standards.. Medical visits and hospitalizations for any reason were from the HIV Research Network, a consortium of high-volume HIV primary care sites. HIV treatment drug regimen efficacies were from clinical guidelines and published sources; data on other drugs used were not available. In a computer simulation model, we projected HIV medical care costs in 2004 U.S. dollars.. From the time of entering HIV care, per person projected life expectancy is 24.2 years, discounted lifetime cost is Dollars 385,200, and undiscounted cost is Dollars 618,900 for adults who initiate ART with CD4 cell count < 350/microL. Seventy-three percent of the cost is antiretroviral medications, 13% inpatient care, 9% outpatient care, and 5% other HIV-related medications and laboratory costs. For patients who initiate ART with CD4 cell count < 200/microL, projected life expectancy is 22.5 years, discounted lifetime cost is Dollars 354,100 and undiscounted cost is Dollars 567,000. Results are sensitive to drug manufacturers' discounts, ART efficacy, and use of enfuvirtide for salvage. If costs are discounted to the time of infection, the discounted lifetime cost is Dollars 303,100.. Effective ART regimens have substantially improved survival and have increased the lifetime cost of HIV-related medical care in the U.S.

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Opportunistic Infections; Anti-Retroviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Cohort Studies; Computer Simulation; Cost-Benefit Analysis; Enfuvirtide; Female; Forecasting; Health Care Costs; Health Services; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Hospitalization; Humans; Inpatients; Life Expectancy; Male; Middle Aged; Multicenter Studies as Topic; Outpatients; Peptide Fragments; Practice Guidelines as Topic; Primary Health Care; RNA, Viral; Time Factors; United States

AIDS is presently treatable, and patients can have a good prognosis due to the success of highly active antiretroviral therapy (HAART), but it is still not curable or preventable. High toxicity of HAART, and the emergence of drug resistance add to the imperative to continue research into new strategies and interventions. Considerable progress in the understanding of HIV attachment and entry into host cells has suggested new possibilities for rationally designing agents that interfere with this process. The approval and introduction of the fusion inhibitor enfuvirtide (Fuzeon) for clinical use signals a new era in AIDS therapeutics. Here we review the crucial steps the virus uses to achieve cell entry, which merit attention as potential targets, and the compounds at pre-clinical and clinical development stages, reported to effectively inhibit cell entry.

Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-HIV Agents; CD4-Positive T-Lymphocytes; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV-1; Humans; Peptide Fragments; Receptors, CCR5

Current HIV entry inhibitors target the binding of the viral envelope glycoprotein gp120 to cellular CD4 and co-receptors, or block a late stage of the fusogenic activation of adjacent gp41. New targets are suggested by the role of cell surface protein disulfide isomerase (PDI), which attaches to the primary receptor CD4 close to the gp120-binding site. This could enable PDI to reduce gp120 disulfide bonds, which triggers the major conformational changes in gp120 and gp41 required for virus entry. Inhibiting cell surface PDI prevents HIV-1 entry. The new potential targets outlined are PDI activity as well as the sites of PDI-CD4 and PDI-gp120 interaction.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CCR5 Receptor Antagonists; CD4 Antigens; Enfuvirtide; Enzyme Inhibitors; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV-1; Humans; Peptide Fragments; Protein Conformation; Protein Disulfide-Isomerases; Receptors, CXCR4

Highly active antiretroviral therapy (HAART) based on combinations of drugs that target key enzymes in the life-cycle of human immunodeficiency virus (HIV) has considerably reduced morbidity and mortality from HIV infection since its introduction in the mid-1990s. However, the growing problem of the emergence of HIV strains that are resistant not only to individual drugs, but to whole drug classes, means that agents with new mechanisms of action are needed. Here, we describe the discovery and development of enfuvirtide (Fuzeon), the first drug to inhibit the entry of HIV-1 into host cells.

Topics: Acquired Immunodeficiency Syndrome; Animals; CD4-Positive T-Lymphocytes; Drug Interactions; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV-1; Humans; Peptide Fragments; Quality of Life

The peptidic antiretroviral enfuvirtide (Fuzeon) is the first clinically approved antiviral fusion inhibitor and the first antiretroviral that must routinely be administered parenterally. Its extracellular activity results both in activity against current drug-resistant strains of HIV-1 and a low potential for systemic toxicities. As a peptide, enfuvirtide also exhibits few interactions with other antiretrovirals and concomitant medications used in HIV disease. Enfuvirtide shows potent antiretroviral activity and significantly improves medical outcomes in highly treatment-experienced patients with HIV-1 infection, but like other antiretrovirals must be given as part of a carefully selected combination regimen to minimise the risk of emergent drug resistance. Despite its subcutaneous route of administration, clinical data indicate that most patients can accept long-term enfuvirtide treatment with little difficulty or impact on daily activities. The only common adverse event associated with enfuvirtide use is injection-site reactions of generally mild-to-moderate severity, which are seldom treatment-limiting.

Topics: Acquired Immunodeficiency Syndrome; Amino Acid Sequence; Cell Fusion; Clinical Trials as Topic; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; Peptides; Virus Physiological Phenomena; Viruses

Despite the overall success of antiretroviral medications in reducing the morbidity and mortality associated with HIV infection, many patients on treatment suffer progressive disease due to intolerance or the development of resistant viral strains. Consequently, considerable research focuses on the development of new classes of antiretroviral agents with mechanisms of action different to the current classes. Enfuvirtide (T-20, pentafuside, Fuzeon), the first drug of a new class of antiretroviral medications known as fusion inhibitors, blocks the fusion of the virus particle with the host target cell. The viral entry process begins with the attachment of viral surface glycoprotein gp120 to the host cell CD4 and chemokine receptor sites. Viral gp41 then undergoes a conformational change enabling fusion of both membranes, a critical step in the viral life cycle. Enfuvirtide is a synthetic peptide that binds to gp41, preventing the conformational change required for membrane fusion. Based on potent in vitro activity, a Phase I clinical trial of intravenous enfuvirtide was conducted that demonstrated a substantial decline in HIV plasma viral load in the highest dose group and no serious adverse effects. Phase II trials evaluated regimens of both continuous subcutaneous infusions and intermittent subcutaneous injections. Intermittent injections were pharmacokinetically superior to continuous infusions and were associated with fewer administration difficulties. For some subjects who added enfuvirtide monotherapy to an already failing regimen, the beneficial effect on viral load reduction appeared short-lived, suggesting the development of resistance. Two large randomised clinical trials comparing "optimised background" (best available, individualised regimens based on patient history and resistance assays) versus optimised background plus enfuvirtide have recently shown a significant virological advantage (approximately 1 log(10) difference from controls) at 24 weeks. In all trials to date, very few significant adverse effects have been seen--minor injection site reactions are frequent, but rarely treatment limiting. Based on these studies, enfuvirtide will likely play a significant role in the treatment of patients with limited treatment options.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Clinical Trials as Topic; Enfuvirtide; HIV Envelope Protein gp41; Humans; Peptide Fragments

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Clinical Trials as Topic; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV-1; Humans; Membrane Fusion; Peptide Fragments

To determine the safety and efficacy of changing enfuvirtide to raltegravir in HIV-1-infected patients with HIV-1 RNA below the level of quantification for at least 6 months on an enfuvirtide-containing antiretroviral regimen.. Prospective, nonrandomized, historical control study.. Patients were recruited from 11 Kaiser Permanente HIV clinics in California. Those patients eligible for inclusion (>or=18 years old, well controlled on antiretroviral medications) had enfuvirtide changed to raltegravir 400 mg, given twice daily orally; all other background antiretrovirals remained unchanged. The primary end point was percentage of patients with HIV-1 RNA below the limit of quantification after 24 weeks of raltegravir therapy. Analyses were by intention to treat.. Fifty-two patients were enrolled in the trial. After 24 weeks of therapy with raltegravir, 49 (94.2%, confidence interval: 1.2% to 15.9%) patients had HIV-1 RNA levels below the limit of quantification. Patients had a median CD4 cell increase of 32 cells per cubic millimeter after 24 weeks of raltegravir therapy. Treatment satisfaction as measured by patient questionnaires improved with the raltegravir-containing regimen. Adverse events were infrequent and generally mild in nature.. In treatment-experienced patients on a stable virologically suppressive enfuvirtide-containing regimen, raltegravir can safely be substituted for enfuvirtide.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome

Enfuvirtide, a HIV-1 membrane fusion inhibitor, is the first viral entry inhibitor approved for the treatment of HIV-1 infected patients in the USA. Parenteral administration of enfuvirtide in clinical trials has been safe and has resulted in significant decreases in plasma viral load, even in the setting of extensive previous treatment and multi-drug resistance to conventional antiretroviral (ARV) therapy. Previous formulations have required two injections administered twice-daily (BID).. The primary objectives of this study were to evaluate the safety, tolerability, and pharmacokinetics of two high-strength 100 mg/ml formulations of enfuvirtide (carbonate [CO(3)] and tromethamine [TRIS] buffer) and of the current formulation (50 mg/ml CO(3) formulation) at doses of 90 mg (deliverable) BID and 67.5 mg (deliverable) BID in treatment-experienced patients.. This was a phase II, multi-center, open-label, sequential cross-over pharmacokinetic, efficacy, and safety study. Study design included two treatment variables; dose (90 mg or 67.5 mg BID) and formulation (A: 50 mg/ml CO(3), B: 100 mg/ml CO(3) or C; 100 mg/ml TRIS).. Forty-six treatment-experienced participants were sequentially enrolled into three treatment cohorts. All cohorts had similar safety profiles and only one patient discontinued due to an adverse event. Pharmacokinetic data indicated that the high-strength 100 mg/ml CO(3) formulation was bioequivalent to the 50 mg/ml CO(3) formulation whereas the TRIS formulation was not. At 48 weeks, 59.1%, 66.7% and 16.7% had <400 copies per milliliter HIV-1 RNA in the 90 MgCO(3), 67.5 MgCO(3) and 90 mg TRIS cohorts with median suppression of HIV-1 RNA of 2.97, 3.48, and 0.87 log(10)copies per milliliter, respectively.. Based upon bioequivalence data and the convenience and similarity in safety and virological effect with the 50 mg/ml formulation, the 100 mg/ml CO(3) formulation was selected for use in clinical efficacy studies of enfuvirtide.

Topics: Acquired Immunodeficiency Syndrome; Adult; CD4 Lymphocyte Count; Chemistry, Pharmaceutical; Cohort Studies; Cross-Over Studies; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Metabolic Clearance Rate; Patient Selection; Peptide Fragments; RNA, Viral; Safety; Viral Load

Enfuvirtide is the first of a new class of antiretroviral agents, the fusion inhibitors.. The primary objective of this analysis was to evaluate the pharmacokinetics of 2.0 mg/kg enfuvirtide in human immunodeficiency virus 1 (HIV-1)-infected children and adolescents when administered in combination with at least 3 other antiretrovirals.. Twenty-five HIV-1-infected pediatric patients (5-16 years of age) enrolled in an ongoing phase I/II study were included in this analysis. Patients received enfuvirtide 2.0 mg/kg sc twice daily (bid) for at least 7 days. Blood samples were collected on day 7, and plasma concentrations of enfuvirtide and its metabolite were measured by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetics measures [Cmax, tmax, Ctrough, and area under the concentration time curve time 0 to 12 hours (AUC12 hours)] were calculated from plasma concentration-time data by standard noncompartmental methods.. There was no significant difference between children and adolescents for enfuvirtide Cmax (6.43 versus 5.88 microg/mL), Ctrough (2.87 versus 2.98 microg/mL) and AUC12 hours (56.1 versus 52.7 hours . microg/mL). Similarly no significant differences were found when the pharmacokinetic measures were compared based on sexual maturity stages. A post hoc regression analysis based on AUC12 hours showed that body weight-adjusted dosing of enfuvirtide provides drug exposure that is independent of age group, body weight and body surface area.. Body weight-adjusted dosing of enfuvirtide, at a dose of 2.0 mg/kg sc bid, in HIV-1-infected pediatric patients at least 5 years of age, provides drug exposure comparable with that previously observed in HIV-1-infected adults after 90 mg sc bid dosing. Drug exposure in children and adolescents is independent of age group, body weight, body surface area and sexual maturity stage.

Topics: Acquired Immunodeficiency Syndrome; Area Under Curve; Child; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV-1; Humans; Male; Peptide Fragments; Protein Binding

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.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dose-Response Relationship, Drug; Enfuvirtide; HIV Envelope Protein gp41; HIV-1; Humans; Injections, Subcutaneous; Middle Aged; Peptide Fragments; RNA, Viral

Fuzeon® (enfuvirtide; Hoffmann-LaRoche, Nutley, NJ) is a parenteral medication prescribed to antiretroviral-experienced HIV patients. Clinicians are frequently concerned when prescribing enfuvirtide to former drug addicts because of the risk of triggering relapse, however, no previous report has described this adverse event. We describe two HIV-infected patients, previously abstinent from injection drug use, who experienced relapse or near-relapse situations after starting treatment with enfuvirtide. Along with the concerns related to adherence and to injection site reactions, clinicians who prescribe enfuvirtide should consider and discuss the risk of triggering relapse among former or recovering drug addicts.

Topics: Acquired Immunodeficiency Syndrome; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; Humans; Injections, Intra-Arterial; Male; Middle Aged; Peptide Fragments; Recurrence; Risk Assessment; Substance Abuse, Intravenous

Albuvirtide (ABT) is a 3-maleimimidopropionic acid (MPA)-modified peptide HIV fusion inhibitor that can irreversibly conjugate to serum albumin. Previous studies demonstrated its in vivo long half-life and potent anti-HIV activity. Here, we focused to characterize its biophysical properties and evaluate its antiviral spectrum. In contrast to T20 (Enfuvirtide, Fuzeon), ABT was able to form a stable α-helical conformation with the target sequence and block the fusion-active six-helix bundle (6-HB) formation in a dominant-negative manner. It efficiently inhibited HIV-1 Env-mediated cell membrane fusion and virus entry. A large panel of 42 HIV-1 pseudoviruses with different genotypes were constructed and used for the antiviral evaluation. The results showed that ABT had potent inhibitory activity against the subtypes A, B and C that predominate the worldwide AIDS epidemics, and subtype B', CRF07_BC and CRF01_AE recombinants that are currently circulating in China. Furthermore, ABT was also highly effective against HIV-1 variants resistant to T20. Taken together, our data indicate that the chemically modified peptide ABT can serve as an ideal HIV-1 fusion inhibitor.

Topics: Acquired Immunodeficiency Syndrome; Amino Acid Sequence; Biophysical Phenomena; Cell Line; Drug Discovery; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV-1; Maleimides; Molecular Sequence Data; Mutation; Peptide Fragments; Peptides; Protein Structure, Secondary; Virus Internalization; Virus Replication

HIV-1 infections lead to a progressive depletion of CD4 cells culminating in AIDS. The coreceptor usage by HIV varies from CCR5 (R5) tropic early in infection to CXCR4 (X4) tropic in later infections. Although the coreceptor switch from R5 to X4 tropic HIV is well associated with progression to AIDS, the role of CCR5 in disease progression especially in patients infected exclusively with R5 isolates throughout the disease remains enigmatic. To better understand the role of CCR5 and R5 tropic HIV envelope in AIDS pathogenesis, we asked whether the levels of CCR5 and/or HIV Env-mediated fusion determine apoptosis of bystander cells. We generated CD4(+) T cell lines expressing varying levels of CCR5 on the cell surface to show that CCR5 expression levels correlate with bystander apoptosis induction. The mechanism of apoptosis involved caspase-3 activation and mitochondrial depolarization and was dependent on gp41 fusion activity as confirmed by fusion-restricted gp41 point mutants and use of the fusion inhibitor T20. Interestingly, lower levels of CCR5 were able to support virus replication in the absence of bystander apoptosis. Our findings suggest that R5 HIV-1-mediated bystander apoptosis is dependent on both CCR5 expression levels as well as fusogenic activity of the Env glycoprotein.

Topics: Acquired Immunodeficiency Syndrome; Apoptosis; Bystander Effect; Caspase 3; CD4-Positive T-Lymphocytes; Enfuvirtide; Enzyme Activation; Gene Expression Regulation; HeLa Cells; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV-1; Humans; Mutation; Peptide Fragments; Receptors, CCR5; Viral Tropism; Virus Replication

The study was carried out in a Hospital of Reference in Infectious Diseases of Ceará, from February 2006 to February 2007, and and aimed at identifying the socio-demographic profile of Enfuvirtide users and their main difficulties/facilities in previous and current treatment scheme. The initial sample analyzed the medical record of 23 patients;18 agreed to participate, comprising the final sample. The descriptive analysis of quantitative data was carried out through the distribution of frequencies and quantitative data, submitted for content analysis. It was observed that 83% were male, 78% were single and the majority was between 30 and 52 years old and, in average, eight years and a half of antiretroviral treatment. From qualitative data, two categories emerged: (1) Previous treatment: difficulties and adversities and (2) Current treatment: from cognition to ability. The difficulties to conduct previous treatments were related to the size and high amount of tablets and side effects. As for facility, the easy drug administration was indicated. Regarding the current treatment, the difficulties were self administration and nodules on the sites where Enfuvirtide was applied and the facilities were absence of gastrointestinal effects and improvement of viral load. It's important to implement an interdisciplinary work that helps patients overcome the difficulties of the treatment, in addition to works in groups in order to better address the difficulties and help increase adhesion to treatment.

Topics: Acquired Immunodeficiency Syndrome; Adult; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; Humans; Male; Middle Aged; Peptide Fragments

We studied gp41 mutations associated with failing enfuvirtide salvage therapy.. This multicentre study involved patients with HIV-1 plasma viral load (pVL) > 5000 copies/mL after at least 3 months of uninterrupted enfuvirtide therapy and with plasma samples available at inclusion (T0), at initial enfuvirtide failure (T1) and at last follow-up visit during continued failing enfuvirtide therapy (T2). The HR-1 and HR-2 domains of the gp41 gene were sequenced at T0, T1 and T2.. Ninety-nine patients were enrolled. At baseline, the median pVL and CD4 cell count were 5.1 log copies/mL and 72 cells/mm(3), respectively. Based on the ANRS Resistance Group algorithm, the proportion of patients harbouring viruses with enfuvirtide resistance mutations increased significantly between T0 and T1. In the HR-1 domain, the V38A/M, Q40H, N42T, N43D and L45M mutations wereselected (P < 0.02). In the HR-2 domain, no mutations were significantly selected during the follow-up. None of the mutations was associated with a CD4 cell count increment.. Mutations selected during failing enfuvirtide salvage therapy are mainly located in the HR-1 domain of the gp41 gene, between codons 38 and 45. No mutations were associated with an increase in the CD4 cell count.

Topics: Acquired Immunodeficiency Syndrome; Adult; Amino Acid Substitution; CD4 Lymphocyte Count; Enfuvirtide; Female; France; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV-1; Humans; Male; Middle Aged; Mutation, Missense; Peptide Fragments; RNA, Viral; Salvage Therapy; Sequence Analysis, DNA; Treatment Outcome; Viral Load

An unexpected dramatic immune recovery was observed in a patient with full-blown AIDS receiving enfuvirtide-based antiretroviral therapy after multiple treatment failures. A complex interplay of viral and host factors, including the control of X4 viruses and proviral burden, may favor immune restoration with HIV neutralizing activity, despite persistent viremia.

Topics: Acquired Immunodeficiency Syndrome; Adult; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Drug Resistance, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV-1; Humans; Mutation; Neutralization Tests; Peptide Fragments; Time Factors; Viremia

The human immunodeficiency virus type 1 fusion inhibitor T-20 (Enfuvirtide, Fuzeon) has recently been introduced into clinical practice. T-20 in combination with HAART efficiently inhibits HIV-1 replication, however T-20 resistance has been reported and the number of confirmed resistant-associated mutations is growing. In this study we aimed to analyze HIV-1 gp41 transmembrane protein (TM) variability and primary resistance to T-20 in plasma viruses from 10 HIV-1 subtype B infected homosexuals. Nine out of ten were documented seroconverters. Nine individuals (including one long time infected therapy naïve individual) were part of four linked virus infection chains. We also examined TM polymorphism in two AIDS patients under HAART and T-20 therapy. Obtained TM amplicons were examined for minor variants by clonal analysis.Sequences polymorphism of the N-terminal regions of the fusion domain (FD) and the heptad repeat 2 (HR2) domain were demonstrated in examined seroconverters. Analysis of the heptad repeat 1 (HR1) domain revealed T-20 resistance in cloned sequences from 3/10 individuals. In two individuals these mutations were present as minor viral quasispecies. Transmission of the resistant virus to the sexual partner was traced in virus infection chain.Baseline TM amplicons (population sequence) and clones from two patients under HAART did not contain T-20 resistance associated mutations. After onset of T-20 therapy only resistant viruses were identified in plasma from the patients. As shown by clonal analysis of plasma from one patient, treatment interruption results in viruses reverting to a T-20-sensitive genotype.

Topics: Acquired Immunodeficiency Syndrome; Amino Acid Sequence; Antiretroviral Therapy, Highly Active; Drug Resistance, Multiple, Viral; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Seropositivity; HIV-1; Humans; Male; Membrane Proteins; Molecular Sequence Data; Peptide Fragments; Polymorphism, Genetic; Protein Structure, Tertiary

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Enfuvirtide; HIV Envelope Protein gp41; Humans; Injections; Peptide Fragments

We studied the effect of entry inhibitors on 58 virus isolates derived during acute and chronic infection to validate these inhibitors in vitro and to probe whether viruses at early and chronic disease stages exhibit general differences in the interaction with entry receptors. We included members of all types of inhibitors currently identified: (i) agents that block gp120 binding to CD4 (CD4-IgG2 and monoclonal antibody [MAb] IgG1b12), (ii) compounds that block the interaction with CCR5 (the chemokine RANTES/CCL5, the small-molecule inhibitor AD101, and the anti-CCR5 antibody PRO 140), (iii) the fusion inhibitor enfuvirtide (T-20), and (iv) neutralizing antibodies directed against gp120 (MAb 2G12) and gp41 (MAbs 2F5 and 4E10). No differences between viruses from acute and chronic infections in the susceptibility to inhibitors targeting the CD4 binding site, CCR5, or fusion or to MAb 2G12 were apparent, rendering treatment with entry inhibitors feasible across disease stages. The notable exceptions were antibodies 2F5 and 4E10, which were more potent in inhibiting viruses from acute infection (P = 0.0088 and 0.0005, respectively), although epitopes of these MAbs were equally well preserved in both groups. Activities of these MAbs correlated significantly with each other, suggesting that common features of the viral envelope modulate their potencies.

Topics: Acquired Immunodeficiency Syndrome; Acute Disease; Adult; Anti-HIV Agents; CCR5 Receptor Antagonists; Chronic Disease; Enfuvirtide; Female; HIV Antibodies; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Regression Analysis

Early in human immunodeficiency virus 1 (HIV-1) infection CCR5-using (R5) viruses predominate. With disease progression, approximately 50% of infected individuals develop viruses able to use CXCR4. In the present work, the evolution of the biological properties of HIV-1 was studied in patients who retain viruses with an R5 phenotype despite AIDS onset. A panel of primary R5 HIV-1 isolates sequentially obtained at an asymptomatic stage and after AIDS diagnosis was examined. The viruses were selected based on our previous observation that R5 variants with reduced sensitivity to RANTES inhibition may appear during disease progression. Biological properties of the early and late R5 viruses, including infectivity, replicative capacity, impact of cationic polymer and sensitivity to inhibition by the entry inhibitors T-20 and TAK-779, were evaluated. R5 viruses isolated after AIDS onset displayed elevated replicative capacity and infectivity, and did not benefit from cationic polymer assistance during infection. Late R5 isolates also exhibited reduced sensitivity to inhibition by T-20 and TAK-779, even though the included patients were naïve to treatment with entry inhibitors and the isolates had not acquired mutations within the gp41 HR1 region. In addition, CD4+ T-cell counts at the time of R5 virus isolation correlated with infectivity, replicative capacity and sensitivity to inhibition by entry inhibitors. The results indicate that R5 HIV-1 variants with augmented replicative capacity and reduced sensitivity to entry inhibitors may be selected for during severe immunodeficiency. At a time when the clinical use of entry inhibitors is increasing, this observation could be of importance in the optimal design of such treatments.

Topics: Acquired Immunodeficiency Syndrome; Amides; CCR5 Receptor Antagonists; Chemokine CCL5; Enfuvirtide; HIV Envelope Protein gp41; HIV-1; Humans; Molecular Sequence Data; Peptide Fragments; Quaternary Ammonium Compounds; Virus Replication

In the last years, highly active antiretroviral therapy has decreased AIDS-associated mortality of patients dramatically. Due to this prolonged lifetime, the emergence of resistance against antiretroviral therapy has increased. Additionally, cross-resistance within the classes of nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI) complicates HIV therapy. Development of new classes of therapeutic agents can help avoiding cross-resistance. Fuzeon, the first agent in the new class of fusion inhibitors, should be combined with as many effective antiretroviral agents as possible.. The course of a 106-week therapy in a patient infected with a multiresistant virus is described.. Fusion inhibitor Fuzeon represents a new option for patients having multiple resistance against HAART.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Resistance, Multiple; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Immune Tolerance; Long-Term Care; Male; Middle Aged; Peptide Fragments

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antiviral Agents; Drug Approval; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments; United States

Topics: Acquired Immunodeficiency Syndrome; Drug Costs; Enfuvirtide; Health Care Rationing; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Injections, Subcutaneous; Peptide Fragments; Prevalence; United States

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Injections, Subcutaneous; Peptide Fragments; RNA, Viral; Virus Replication

Topics: Acquired Immunodeficiency Syndrome; Amino Acid Sequence; Anti-HIV Agents; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Molecular Sequence Data; Peptide Fragments; Viral Fusion Proteins

Entry-inhibitors represent a new option in antiretroviral therapy. They prevent infection of HIV target-cells. According to their mechanism of action they can be divided into three groups: attachment-inhibitors, corezeptor-antagonists and fusion-inhibitors. The fusion-inhibitor T-20 (Enfuvirtide) will be the first substance to be licensed in 2003. It has been shown that entry-inhibition is a realistic goal for clinical use. Until now T-20 was mainly added to an optimized background regimen in intensively pretreated patients. To achieve the best efficacy a combination of substances with only slight preexisting resistance seems to be favorable. Further efforts in providing orally applicable drugs with little potential for developing resistance and with synergistic effects are required.

Topics: Acquired Immunodeficiency Syndrome; Drug Administration Schedule; Drug Approval; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; Humans; Injections, Subcutaneous; Peptide Fragments

An in-depth look at why the AIDS Drug Assistance Program is running out of money in many states--and what might be done to improve the situation.

Topics: Acquired Immunodeficiency Syndrome; Enfuvirtide; Financing, Government; HIV Envelope Protein gp41; HIV Fusion Inhibitors; Humans; Medical Assistance; Peptide Fragments

Topics: Acquired Immunodeficiency Syndrome; Amino Acid Substitution; Anti-HIV Agents; CD4-Positive T-Lymphocytes; Enfuvirtide; Evolution, Molecular; HIV Envelope Protein gp41; HIV-1; Humans; Peptide Fragments; Receptors, CCR5; Sequence Analysis, DNA; Viremia

Topics: Acquired Immunodeficiency Syndrome; Administration, Cutaneous; Anesthetics, Local; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Argentina; Asia; Attitude to Health; Awareness; Child; Child Health Services; Congresses as Topic; Developing Countries; Disease Outbreaks; Enfuvirtide; Female; Health Services; HIV Envelope Protein gp41; HIV-Associated Lipodystrophy Syndrome; Homosexuality, Male; Humans; Lidocaine; Male; Peptide Fragments

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Design; Drug Industry; Enfuvirtide; HIV Envelope Protein gp41; HIV Protease Inhibitors; Humans; Peptide Fragments; Pharmacogenetics; United States

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials, Phase II as Topic; Enfuvirtide; HIV Envelope Protein gp41; HIV-1; Humans; Peptide Fragments; Treatment Outcome; Viral Load

Succinyl and 3'-substituted glutaryl betulin derivatives showed stronger anti-HIV activity and higher therapeutic index (TI) values than their dihydrobetulin counterparts, with ratios of 1.2:1 to 15:1 (cf. 7 and 15, 9 and 17, 10 and 18, 11 and 19, and 12 and 20). For various 3'-substituted glutaryl compounds, the order of anti-HIV effects, from strong to weak inhibition, was 3',3'-dimethyl, 3'-methyl, 3'-ethyl-3'-methyl, followed by 3',3'-tetramethylene glutaryl derivatives (10 > 9 > 11 > 12, 18 > 17 > 19 > 20). The most potent compound, 10, has two 3',3'-dimethylglutaryl groups and displays significant anti-HIV potency with an EC50 value of 0.000 66 microM and a TI of 21 515. Results for compounds (22 and 23) without a C-3 acyl group confirmed the importance of the C-3 acyl group to the anti-HIV effect. With 3',3'-tetramethylene glutaryl derivatives, triacyl 29 showed stronger inhibition than diacyl 12; in contrast, 3',3'-dimethylglutaryl compounds displayed opposite results. 3-Keto compounds (35 and 36) and 2,3-dihydro compounds (39 and 40) had EC50 values in the range of 4.3-10.0 microM, suggesting that A ring modification led to decreased potency. The reduced activity of amide (33 and 34), ester (41), and oxime (42) analogues suggested that the orientation and linkage of the C-3 acyl side chain play crucial roles in the potent anti-HIV activity. Finally, replacing the C-28 acyl group with a bulky non-carboxylic group produced a less potent compound (44). In the study of mechanism of action, our results indicated that fusion is not the primary target for the anti-HIV activity of 10. It appears to inhibit HIV replication at a late stage of the viral life cycle, i.e., after viral protein synthesis.

Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-HIV Agents; Cell Fusion; Cell Line; Glutarates; HeLa Cells; HIV-1; Humans; Lymphocytes; Mice; Structure-Activity Relationship; Triterpenes; Virus Replication

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Therapy, Combination; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Infections; HIV Seropositivity; Humans; Peptide Fragments

Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-HIV Agents; Enfuvirtide; HIV Envelope Protein gp41; HIV-1; Humans; Investigational New Drug Application; Mice; Peptide Fragments; Research; Time Factors; United States; United States Food and Drug Administration

Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-HIV Agents; Enfuvirtide; HIV Envelope Protein gp41; HIV-1; Mice; Mice, SCID; Peptide Fragments