enfuvirtide and HIV-Infections

Peptides derived from the C-terminal heptad repeat 2 region of the HIV-1 gp41 envelope glycoprotein, so-called C peptides, are very potent HIV-1 fusion inhibitors. Antiviral genes encoding either membrane-anchored (ma) or secreted (iSAVE) C peptides have been engineered and allow direct in vivo production of the therapeutic peptides by genetically modified host cells. Membrane-anchored C peptides expressed in the HIV-1 target cells by T-cell or hematopoietic stem cell gene therapy efficiently prevent virus entry into the modified cells. Such gene-protection confers a selective survival advantage and allows accumulation of the genetically modified cells. Membrane-anchored C peptides have been successfully tested in a nonhuman primate model of AIDS and were found to be safe in a phase I clinical trial in AIDS patients transplanted with autologous gene-modified T-cells. Secreted C peptides have the crucial advantage of not only protecting genetically modified cells from HIV-1 infection, but also neighboring cells, thus suppressing virus replication even if only a small fraction of cells is genetically modified. Accordingly, various cell types can be considered as potential in vivo producer cells for iSAVE-based gene therapeutics, which could even be modified by direct in vivo gene delivery in future. In conclusion, C peptide gene therapeutics may provide a strong benefit to AIDS patients and could present an effective alternative to current antiretroviral drug regimens.

Topics: Animals; Enfuvirtide; Genetic Therapy; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Membrane Fusion; Peptide Fragments; Virus Internalization

The use of synthetic peptides as HIV-1 inhibitors has been the object of research over recent years. A large number of peptides that affect different stages of the HIV-1 life cycle have been and continue to be studied due to their possible clinical application in the fight against HIV-1 infection. The main advantages of synthetic peptides as therapeutic agents are their low systemic toxicity, the fact that structural modifications can be made to them and their resulting capacity to mimic certain substrates or epitopes. HIV-1-inhibiting peptides have been identified and/or developed using different methods. Some therapeutic peptides such as enfuvirtide-already approved for clinical use-are derived from HIV-1 itself. Others are natural peptides such as chemokines, defensins or the "virus inhibitory peptide"; while still others have been designed and synthesized based on crystallographic data on HIV-1 proteins or from peptide libraries. Initial attempts at therapeutic applications focused on HIV-coded enzymes (reverse transcriptase, protease and, more recently, integrase). However, structural HIV proteins and, more specifically, the mechanisms that involve the virus in cell infection and replication are now also considered therapeutic targets. Several chemical strategies to improve both the stability of peptides and their pharmacokinetics, including prolonging their half-life, have recently been described in the literature. There is growing an interest in inhibitors that prevent HIV entry into the host cell (fusion inhibitors) which could lead to the development of new antiviral agents. Knowledge of the mechanism of action of fusion inhibitors is essential not only for the development of future generations of entry inhibitors, but also to gain an understanding of the form and kinetics of membrane fusion induced by the virus. The physico-chemical processes involved at the interface between the lipid surface of cells and enveloped viruses (such as HIV-1) are essential to the action of peptides that prevent HIV-1 entry into the host cell. The interaction of these peptides with biological membranes may be related to their inhibition efficiency and to their mechanism of action, as the HIV-1 gp41 glycoprotein is bound and confined between the cellular membrane and the viral envelope.

Topics: Amino Acid Sequence; Clinical Trials as Topic; Enfuvirtide; Half-Life; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Models, Molecular; Molecular Sequence Data; Peptide Fragments; Peptide Library; Protein Structure, Tertiary; Structure-Activity Relationship; Virus Internalization

HIV resides within anatomical 'sanctuary sites' where local drug exposure and viral dynamics may differ significantly from the systemic compartment. Widespread implementation of antiretroviral therapy has seen a significant decline in the incidence of mother-to-child transmission (MTCT) of HIV. In addition to suppression of maternal plasma/genital viral loads, antiretroviral agents that cross the placenta and achieve adequate concentrations in the fetal compartment may exert a greater prophylactic effect. Penetration of antiretrovirals in the fetal compartment is expressed by accumulation ratios derived from the measurement of drug concentrations in paired maternal plasma and umbilical cord samples. The nucleoside analogues and nevirapine accumulate extensively in cord blood and in the surrounding amniotic fluid, whereas the protease inhibitors (PIs) exhibit low-to-moderate placental accumulation. Early data suggest that high placental/neonatal concentrations are achieved with raltegravir, but to a lesser extent with etravirine and maraviroc (rank order of accumulation: raltegravir/nucleoside reverse transcriptase inhibitor [tenofovir > zidovudine/lamivudine/emtricitabine/stavudine/abacavir] > non-nucleoside reverse transcriptase inhibitor [nevirapine > etravirine] > PI > maraviroc/enfuvirtide). More comprehensive in vivo pharmacokinetic data are required to justify the potential use of these agents as safe and effective options during pregnancy.

Topics: Adenine; Adult; Amniotic Fluid; Anti-HIV Agents; Cyclohexanes; Enfuvirtide; Female; Fetal Blood; Fetus; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Maraviroc; Nevirapine; Organophosphonates; Peptide Fragments; Placenta; Pregnancy; Pregnancy Complications, Infectious; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Tenofovir; Triazoles; Viral Load; Zidovudine

Infection of target cells by HIV is a complex, multi-stage process involving attachment to host cells and CD4 binding, coreceptor binding, and membrane fusion. Drugs that block HIV entry are collectively known as entry inhibitors, but comprise a complex group of drugs with multiple mechanisms of action depending on the stage of the entry process at which they act. Two entry inhibitors, maraviroc and enfuvirtide, have been approved for the treatment of HIV-1 infection, and a number of agents are in development. This review covers the entry inhibitors and their use in the management of HIV-1 infection. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Topics: Cyclohexanes; Drug Resistance, Viral; Enfuvirtide; History, 20th Century; History, 21st Century; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Maraviroc; Peptide Fragments; Triazoles

Drug resistance is a major challenge in the treatment of HIV infection. Enfuvirtide is the first entry inhibitor to have been approved for clinical use.. Relevant information through searches of MEDLINE (1998 to June 2010) and meeting abstracts of major HIV/AIDS conferences (2003 - June 2010) using the search terms 'enfuvirtide', 'T-20' and 'fusion inhibitor'.. Enfuvirtide blocks HIV fusion to host cells. It works against the different HIV-1 variants but is not active against HIV-2. The recommended dosage of enfuvirtide is 90 mg b.i.d. subcutaneously. The two large Phase III pivotal clinical trials TORO 1 and 2 showed that enfuvirtide is an effective therapeutic option as rescue therapy in combination with other active antiretroviral drugs. Resistance to enfuvirtide is conferred by mutations in the HR1 region of gp41. Single and double mutations have been shown to result in high-level resistance to enfuvirtide. Postmarketing studies have been helpful to define more precisely the place of enfuvirtide in the sequence of antiretroviral therapy.. The emergence of new compounds and new classes of drugs, highly active against multiresistant virus but more convenient to administer than enfuvirtide, will probably prevent the extensive use of enfuvirtide. This drug remains attractive in some subgroups of patients because of its excellent systemic tolerance and the lack of interactions with the major cytochrome P450 isoenzymes.

Topics: Animals; Clinical Trials, Phase III as Topic; Drug Interactions; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments; Salvage Therapy

This review discusses recent progress in the development of anti-HIV agents, with emphasis on small molecule HIV-1 entry inhibitors. The entry inhibitors primarily target HIV-1 envelope glycoproteins or the cellular receptors, CD4 and chemokine receptors. Two of the entry inhibitors, enfuvirtide and maraviroc, have been approved by the US FDA for AIDS therapy. The drug resistance associated with some of the entry inhibitors will also be discussed.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; CD4 Antigens; Cyclohexanes; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Maraviroc; Molecular Structure; Peptide Fragments; Receptors, CCR5; Receptors, Chemokine; Receptors, CXCR4; Triazoles

HIV-1 fusion inhibitors are a new class of anti-HIV compounds, which block the entry of HIV into target cells through preventing the fusion between viral and cell plasma membrane and thus interrupt the initial steps of viral replication. T-20 (enfuvirtide), which has been clinically approved as the first fusion inhibitor of HIV-1 by U.S. FDA in 2003, can suppress replication of HIV variants with multi-drug resistance to reverse transcriptase and protease inhibitors. Peptides and small molecules display potent anti-HIV fusion activities by targeting gp41 thus inhibit its fusogenic function. In recent years, with the development of studies on the molecular mechanism of HIV membrane fusion process and the function of gp41, many new fusion inhibitors are found and some have been in advanced clinical trials. This review discusses recent progress in the development of HIV-1 fusion inhibitors targeting the gp41.

Topics: alpha 1-Antitrypsin; Anti-HIV Agents; Drug Resistance, Multiple; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; Peptides; Recombinant Fusion Proteins; Virus Replication

In the two decades since AZT was first approved for clinical use in 1987, 24 additional antiretroviral agents have been approved. They include 7 nucleoside analogs, a nucleotide analog and 4 non-nucleoside reverse transcriptase inhibitors, 10 protease inhibitors, 2 entry inhibitors and an integrase inhibitor. More than 20 investigational agents are currently being studied in clinical trials. Highly active antiretroviral therapy (HAART), which involves a combination of anti-HIV-1 drugs, is extremely effective in suppressing HIV-1 replication and increasing CD4+ number and results in substantial reductions in HIV-1-related morbidity and mortality. In last 20 years, much has been learned about resistance to antiretroviral drugs, drug interactions and metabolic complications of antiviral drug use. Drugs are now selected on the basis of resistance tests and on the risk of specific drug complications in individual patients. As a result, decisions about the therapy of HIV/AIDS have become personalized and are made on a patient-by-patient basis. With appropriate medical management, a person with HIV-1 now has the possibility of a nearly normal life expectancy.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cyclohexanes; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Maraviroc; Molecular Structure; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; Saquinavir; Triazoles; Virus Replication; Zidovudine

The entry of viruses into target cells involves a complex series of sequential steps, with opportunities for inhibition at every stage. Entry inhibitors exert their biological properties by inhibiting protein-protein interactions either within the viral envelope (Env) glycoproteins or between viral Env and host-cell receptors. The nature of resistance to entry inhibitors also differs from compounds inhibiting enzymatic targets due to their different modes of action and the relative variability in Env sequences both temporally and between patients. Two drugs that target HIV-1 entry, enfuvirtide and maraviroc, are now licensed for treatment of HIV-1 infection. The efficacy of these drugs validates entry as a point of intervention in viral life cycles and, in the context of HIV treatment, contributes to the growing armamentarium of antivirals which, in multidrug combinations, can effectively inhibit viral replication and prevent disease progression.

Topics: Animals; Chemokines; Cyclohexanes; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Maraviroc; Peptide Fragments; Triazoles; Virus Attachment; Virus Internalization

The purpose of this review is to discuss recent pharmacological, virological, and clinical data that concern enfuvirtide usage in different antiretroviral combinations.. Randomized, recent trials in multidrug-experienced patients suggest that antiretroviral combinations with enfuvirtide have excellent virological responses with new antiretroviral compounds, including darunavir, etravirine, raltegravir, vicriviroc, and maraviroc. Trials confirm long-term safety, in spite of moderate injection-site reactions or pain, and lack of significant interactions. Preliminary data suggest that switching from enfuvirtide to raltegravir is effective and using enfuvirtide in prophylaxis of mother-to-child transmission is well tolerated. To administer enfuvirtide in an intensification strategy in antiretroviral-naïve or experienced populations may accelerate virological decline.. Dosage adaptations to renal insufficiency are not necessary with enfuvirtide. Spinal fluid concentrations and ombilic cord passage are negligible. Durability of virological responses with enfuvirtide in combinations has been confirmed, in spite of injection-site reactions and twice daily subcutaneous administration. Enfuvirtide should be used with at least one other fully active drug in optimized background therapy in multidrug-experienced populations, a possible exception being with entry inhibitors, which may further benefit from the addition of a third active drug. Data concerning enfuvirtide in antiretroviral combinations show accelerated viral load decline, and the possibility of switching from enfuvirtide to raltegravir without modification of optimized background therapy.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Chemoprevention; Clinical Trials as Topic; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Peptide Fragments; Treatment Outcome

To provide an update on viral entry inhibitors focusing on recently published clinical trials, the routine clinical use of these medications, and future drug candidates.. Clinical trials and cohort studies support the efficacy of both enfuvirtide and maraviroc in the management of treatment-experienced patients. In clinical practice, tolerability issues, particularly injection site reactions, have limited the clinical use of enfuvirtide. Providers should be aware of the need for tropism determination and dosing requirements for maraviroc. The novel chemokine (C-C motif) receptor 5-blocking agent, vicriviroc, has shown promise and is currently in phase III clinical development.. The rapid pace of scientific discovery and pharmaceutical development has led to the release of several novel and well tolerated antiretroviral agents, with activity against resistant isolates. Entry inhibitors remain a critical therapeutic option for treatment-experienced patients. Providers need to be familiar with these agents, and future drug development should be encouraged.

Topics: CCR5 Receptor Antagonists; Cyclohexanes; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Maraviroc; Peptide Fragments; Piperazines; Pyrimidines; Salvage Therapy; Triazoles; Virus Internalization

The development of new protease inhibitors, new non-nucleoside reverse transcriptase inhibitors and novel therapeutic drug classes has dramatically changed the approach to managing HIV-1 patients with multidrug resistant virus. This has led many clinicians to reevaluate the clinical utility of enfuvirtide.. To summarize recent literature on enfuvirtide and to reassess enfuvirtide's role in the management of HIV-1 infection.. MEDLINE (1990 to February Week 2 2008) and EMBASE (1990 to 2008 week 8) databases were searched using the following terms: 'enfuvirtide', 'Fuzeon', 'T20', 'HIV fusion inhibitors', and 'HIV entry inhibitor'; limits: English language. Reference lists of articles deemed relevant were hand searched for additional publications. Significant abstracts from recent international HIV conferences were also identified.. Enfuvirtide can optimize the response to new combinations of HIV-1 drug regimens in multiresistant patients. Its inclusion as an active agent is effective but use is impacted by its high cost, inconvenient route of administration and cosmetic side-effect profile.

Topics: Clinical Trials, Phase III as Topic; Drug Administration Schedule; Drug Interactions; Drug Resistance, Multiple, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; Product Surveillance, Postmarketing; Quality of Life

Antiretroviral rescue therapy has been revolutionized by the development of new drugs in the last few years: enfuvirtide (a fusion inhibitor), tipranavir/ritonavir (a high genetic barrier protease inhibitor), darunavir/ritonavir (a high genetic barrier protease inhibitor), etravirine (a non-nucleoside reverse transcriptase inhibitor active against nevirapine- and efavirenz- resistant HIV), maraviroc (a CCR5 coreceptor inhibitor) and raltegravir (an integrase inhibitor). The use of these drugs in rescue regimens has allowed the goal of antiretroviral rescue therapy to be the same as that in treatment naive-patients: to achieve a viral load lower than 50 copies of RNA of HIV/ml. Raltegravir is the first integrase inhibitor available for clinical use in Spain. This drug is primarily metabolized through UGT1A1-mediated glucuronidation and consequently has a low potential for interactions with drugs metabolized by the cytochrome P450 pathway. Raltegravir has been demonstrated to have high efficacy in two large clinical trials of rescue therapy, especially when combined with darunavir/ritonavir and enfuvirtide. Preliminary data suggest that raltegravir could also be an effective drug in treatment-naive patients and as substitution therapy in patients with toxicity due to boosted protease inhibitor therapy. The drug's unusual mechanism of action has reopened the possibility of a positive effect on latent HIV reservoirs.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclohexanes; Darunavir; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; Forecasting; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; Humans; Maraviroc; Nitriles; Peptide Fragments; Pyridazines; Pyridines; Pyrimidines; Pyrones; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Sulfonamides; Triazoles

Once patients have a triple class virological failure, their treatment options are limited and there is an increased risk of death. In order to construct active treatment regimens, new potent antiretroviral agents are available for these patients. The virological target in patients with treatment failure is now plasma HIV RNA level below 50 copies/ml when 2 or more potent drugs are identified. If at least two active drugs cannot be identified, the current regimen should be maintained until new drugs become available, assuming that there is an immunological and clinical stability, in order to avoid the use of a single-active drug that usually leads to rapid development of resistance, further limiting the future treatment options. In this article, the current state of knowledge about these new agents available and the guidelines of main societies are reviewed.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Darunavir; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; Humans; Organic Chemicals; Peptide Fragments; Practice Guidelines as Topic; Pyridines; Pyrones; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; RNA, Viral; Sulfonamides

The first appearance of lipid rafts, or lipid rafts-like structure, was occasionally observed by cryo-electronic microscopy in 1980s as cavity, such as caveolae. However, the fully understanding of lipid raft was attributed by the studies of T cell activation, virus entry/budding, and other membrane events. During the interaction of T cell and antigen presenting cell, a highly organized structure is formed at the interface of the two cells, where cholesterol and sphingolipids are enriched, and form a liquid ordered phase that facilitates the signaling proteins on and off. Lipid rafts are also involved in virus entry and assembly. In this review, we will discuss cholesterol-sphingolipid floating microdomain, the lipid raft as a unique compartment of the plasma membrane, with biological functions that ensure correct intracellular traffic of proteins and lipids, such as protein-protein interactions by concentrating certain proteins in these microdomains, while excluding others. We also discuss the disruption of lipid rafts is related to different diseases and aging, and we especially exploit the lipid rafts as pharmaceutical targets for anti-virus and anti-inflammation, particularly a new approach to control HIV infection for AIDS prevention and protection by inhibition or disruption of lipid rafts.

Topics: Anticholesteremic Agents; Autoimmune Diseases; Cell Membrane; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Inflammation; Lymphocyte Activation; Membrane Lipids; Membrane Microdomains; Peptide Fragments; T-Lymphocytes; Virus Assembly; Virus Internalization

Topics: Clinical Trials as Topic; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Mutation; Peptide Fragments; Viremia

Enfuvirtide is a high-cost, parenterally administered drug commonly used in late phases of HIV infection, when its efficacy may be compromised. To optimize enfuvirtide use, consensus recommendations for this purpose have been formulated by 247 physicians attending patients with HIV infection in Spain. A literature review was performed in which grades of evidence and recommendations were defined according to the origin of the data (randomized clinical trials, non-randomized studies, expert opinion). Twenty-eight local consensus meetings were held between May and September 2005 to discuss the most important aspects related to the use of enfuvirtide, following a pre-established system used in all the meetings. The main conclusions were as follows: a) enfuvirtide use is often excessively delayed and is given to patients with little chance of treatment success; b) enfuvirtide is indicated in patients who require antiretroviral treatment and for whom an optimum treatment with three other fully effective drugs cannot be designed; c) the most important prognostic factor is the availability of at least one other completely active drug; d) there is no infallible method to avoid the development of local reactions, but measures are available to decrease their incidence and severity; and e) patient counseling and training for correct administration of the drug are essential to improve adherence, the repercussions of local reactions and, of course, the efficacy of the treatment.

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Patient Compliance; Peptide Fragments; Prognosis; Salvage Therapy

The need for new classes of antiretroviral drugs has become apparent because of increasing concern about the long-term toxic effects of existing drugs, the need to combat HIV-1 variants that are resistant to treatment, and the frequency of treatment change in drug-experienced patients. Currently, most regimens are combinations of inhibitors of two viral enzymes--reverse transcriptase and protease. Nevertheless, several steps in the HIV replication cycle are potential targets for intervention. These steps can be divided into entry steps, in which viral envelope glycoproteins and their receptors are involved, and postentry steps, involving viral accessory gene products and the cellular proteins with which they interact. New treatment options target viral entry into the cell. These treatments include the HIV fusion inhibitor enfuvirtide, and new HIV coreceptor antagonists in advanced stages of clinical development or in different stages of preclinical development. Here, we review the development of new HIV entry inhibitors, their performance in clinical trials, and their possible role in anti-HIV therapy.

Topics: Anti-HIV Agents; Benzylamines; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclams; Enfuvirtide; Heterocyclic Compounds; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; Virus Replication

In this review, we will describe several recent HIV-1 studies in which a drug-dependent virus variant was selected. A common evolutionary route to the drug-dependence phenotype is proposed. First, the selection of a drug-resistance mutation that also affects the function of the targeted viral protein. Second, a compensatory mutation that repairs the protein function, but in the presence of the drug, which becomes an intrinsic part of the mechanism. The clinical relevance of drug-dependent HIV-1 variants is also discussed.

Topics: Anti-HIV Agents; Drug Resistance; Enfuvirtide; Genetic Variation; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; Phenotype; Viral Envelope Proteins

Entry inhibitors represent a new generation of antivirals for the treatment of HIV infection. Several compounds which block the attachment of HIV gp120 to either the CD4 T cell receptor or the CCR5/CXCR4 co-receptors are currently in clinical development. Most of these compounds have different molecular structures and specific mechanisms of action. These agents are eagerly awaited by a growing number of patients carrying viruses resistant viruses to many of the current available reverse transcriptase and protease inhibitors. For enfuvirtide, the first and, so far, only entry inhibitor approved for clinical use, the main mechanism of resistance is the selection of changes within a 10 amino acid segment encompassing residues 36-45 within the HR1 region of gp41. For other entry inhibitors, multiple changes in different gp120 domains (V1, V2, V3, C2 and C4) have been associated with loss of susceptibility to these agents, although in most cases with limited cross-resistance.

Topics: Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; Receptors, CCR5; Receptors, CXCR4

Class I viral fusion proteins have an important role in the fusion of viral membranes with host cell membranes, a critical step in the viral life-cycle. These proteins all have similar structural features and form six-helix bundles in their fusogenic form, a general mechanism of action for virus-cell fusion. The successful discovery of peptide-based inhibitors of fusion proteins, in addition to the US Food and Drug Administration approval of one of these inhibitors as an anti-HIV-1 drug, confirmed that the inhibition of six-helix bundle formation is a viable strategy for identifying antiviral drugs. Because peptide-based drugs have several limitations, research has been undertaken to identify potent small-molecule inhibitors of six-helix bundle formation in a variety of viruses, including HIV-1, human respiratory syncytial virus and measles virus. Small-molecule inhibitors that disrupt six-helix bundle formation and prevent viral infection have been identified. This review will focus on the discovery of these small-molecule inhibitors.

Topics: Aminophenols; Animals; Antiviral Agents; Benzeneacetamides; Benzimidazoles; Drug Design; Drug Evaluation, Preclinical; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Measles virus; Peptide Fragments; Protein Structure, Secondary; Respiratory Syncytial Virus, Human; Viral Fusion Proteins

As we approach the completion of the first 25 years of the human immunodeficiency virus (HIV) epidemic, there have been dramatic improvements in the care of patients with HIV infection. These have prolonged life and decreased morbidity. There are twenty currently available antiretrovirals approved in the United States for the treatment of this infection. The medications, including their pharmacokinetic properties, side effects, and dosing are reviewed. In addition, the current approach to the use of these medicines is discussed. We have included a section addressing common comorbid conditions including hepatitis B and C along with tuberculosis.

Topics: Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Enfuvirtide; Female; Genotype; Hepatitis B; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Mutation; Peptide Fragments; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications, Infectious; Protease Inhibitors; Reverse Transcriptase Inhibitors; Ritonavir; Zidovudine

The human immunodeficiency virus (HIV) was discovered in 1982, but treatment strategies were not introduced until 5 years later. Early regimens consisted of one or two drugs and often led to treatment failure. Since the advent in 1995 of highly active antiretroviral therapy (HAART), which consists of at least three agents, a dramatic improvement has been seen in the number of patients attaining undetectable viral loads, improved CD4 counts, and improved survival. However, early HAART often consisted of drugs with complex dosing schedules, strict food requirements, treatment-limiting adverse effects, and the need to take 16-20 pills/day. These treatment barriers often led to patient nonadherence, with subsequent treatment failure and development of resistant strains. The CD4 count and viral load are the most important surrogate markers used to determine if treatment is indicated. Current guidelines suggest starting treatment in patients who are symptomatic with an acquired immunodeficiency syndrome-defining illness regardless of CD4 count or viral load, as well as in asymptomatic patients with a CD4 count of 350 cells/mm(3) or below. In patients with CD4 counts above 350 cells/mm(3) and viral loads above 100,000 copies/ml, some clinicians prefer to defer treatment, whereas others will consider starting therapy; treatment is deferred in patients with CD4 counts above 350 cells/mm(3) and viral load s below 100,000 copies/ml. If therapy is started, the selection of appropriate agents is based on comorbidities (liver disease, depression, cardiovascular disease), pregnancy status, adherence potential (dosage regimen, pill burden, dosing frequency), food restrictions (dosing with regard to meals), adverse drug effects, and potential drug-drug interactions. Within the last 8 years, newer antiretroviral agents have focused on ways to improve adherence, such as convenient dosing (fewer pills), pharmacokinetic and formulation changes to reduce dosing frequency or pill burden, and coformulated dosage forms that contain two or three drugs in one convenient pill. Other improvements include increased potency of newer agents, agents sensitive to a highly resistant virus, improved adverse-effect profile (e.g., less gastrointestinal effects, improved lipid profiles), as well as protease inhibitor boosting with ritonavir, which takes advantage of the potent cytochrome P450 inhibitory action of ritonavir. This review focuses on the concepts of antiretroviral therapy, barrier

Topics: Adenine; Animals; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Carbamates; Clinical Trials as Topic; Deoxycytidine; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Drugs, Investigational; Emtricitabine; Enfuvirtide; Furans; HIV Envelope Protein gp41; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Oligopeptides; Organophosphates; Organophosphonates; Patient Compliance; Peptide Fragments; Pyridines; Pyrones; Reverse Transcriptase Inhibitors; Sulfonamides; Tenofovir

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.

Topics: Adult; Antiretroviral Therapy, Highly Active; Child; Drug-Related Side Effects and Adverse Reactions; Enfuvirtide; Forecasting; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Reverse Transcriptase; Humans; Peptide Fragments; Randomized Controlled Trials as Topic; Treatment Outcome

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

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.

Topics: Amino Acid Sequence; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Interactions; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Molecular Sequence Data; Peptide Fragments

Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) is having a devastating impact on African men, women and children. Antiretroviral treatment of children has lagged behind that of adults in Africa and globally. Fortunately, several national and international initiatives are helping to catalyze access of HIV-infected children to treatment. In general, the principles of antiretroviral treatment are the same for resource-rich and resource-poor settings. However, the more rapid progression of HIV disease often observed among children in Africa and some other resource-poor settings may argue for a more aggressive approach to initiation of treatment. In addition, numerous barriers to treatment of HIV-infected children in Africa and other resource-poor settings exist and must be overcome, including the expense of antiretroviral medications, lack of pediatric drug formulations, and poor human capacity and infrastructure for treatment administration. The 2.2 million African children currently living with HIV/AIDS, and many more living in poor countries on other continents, are dependent on all of us to work creatively to overcome barriers to the large-scale implementation of programs for health-restoring, life-prolonging antiretroviral treatment.

Topics: Adolescent; Africa; Anti-Retroviral Agents; Child; Developing Countries; Drug Administration Schedule; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Infant; Integrase Inhibitors; Patient Compliance; Peptide Fragments; Withholding Treatment

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.

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections, Subcutaneous; Peptide Fragments

Enfuvirtide is a new class of antiviral drug, fusion inhibitors, which interferate with penetration of HIV-1 in the cells. Enfuvirtide exhibits potent and selective inhibition of membrane of viral and cells. It specifically inhibits the function of the gp41 transmembrane glycoprotein of HIV-1. Enfurvitide showed significantly efficacy in the combination with other antiviral drugs in early stadium of HIV infection and in patients with antiretroviral resistention. Local injection site reactions are the most common adverse events associated with enfurvitide. However, the need for subcutaneous application of enfurvitide is a distinct disadvantage, especially in patients who are already burdened by complex oral therapy.

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments

HIV-1, causative agent of acquired immunodeficiency syndrome, was identified in the early 1980s . The plague quickly spread throughout the world and today 40 million people are living with HIV/AIDS. The first anti-HIV drug "zidovudine", was discovered in 1985, and many other inhibitory compounds have been developed successfully in the last decade. Today, three classes 17 antiretroviral drugs are available in Japan. This article overviews the history of anti-HIV drug discovery, present HIV-1 treatment, and on-going drug discovery.

Topics: Anti-HIV Agents; Drug Design; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Peptide Fragments; Receptors, Chemokine; Reverse Transcriptase Inhibitors

Several new antiretroviral agents have been introduced into pediatric and adult use. This review will summarize information about these new agents and other recent advances in the care of HIV-infected children.. New drugs like tenofovir, emtricitabine, and enfuvirtide are being rapidly introduced into antiretroviral treatments for adult patients. In addition, some well-established drugs are being modified to make them more convenient (specifically didanosine and stavudine). Unfortunately, pediatric data lag for these new agents, in some cases because of complicated pharmacokinetics in children. At the same time, critical information on how to use established drugs like nelfinavir and efavirenz in younger children is slowly becoming available. Although antiretroviral treatment in children has often been initiated at standard doses of milligrams per kilogram, and susceptibility to drug was presumed in individuals without a previous history of exposure, recent data show that some primary infections are caused by drug-resistant virus, and there is a tremendous variability in serum drug levels in children. Researchers and clinicians should consider the role of baseline antiretroviral susceptibility testing and therapeutic drug monitoring to identify the optimal treatment for each child.. New therapeutic options for children with HIV infection are becoming available as the pharmacokinetics and best strategies for use of newer drugs are studied.

Topics: Adenine; Anti-Bacterial Agents; Anti-HIV Agents; Child; Deoxycytidine; Didanosine; Drug Therapy, Combination; Emtricitabine; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Microbial Sensitivity Tests; Organophosphonates; Organophosphorus Compounds; Peptide Fragments; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Stavudine; Tenofovir

The number of antiretroviral-experienced HIV patients with multiple resistances against the currently available antiretroviral drug classes is increasing substantially. Therapeutic options for this specific group of patients are limited. The fusion inhibitor enfuvirtide represents the first new therapeutic option from a new drug class for this patient population. An optimized background therapy with remaining antiviral activity appears essential in order to avoid resistance development against enfuvirtide. Despite the high price of enfuvirtide, cost-effectiveness and increase in quality of life have been demonstrated in patients achieving virological control under optimized background and enfuvirtide therapy. In this article, the characteristics and clinical perspectives of fusion inhibitors are presented and discussed.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Multiple, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Treatment Failure

Drug resistance continues to be a major challenge in the treatment of HIV-1 infection. Virtually all currently available antiretroviral medications inhibit the viral reverse transcriptase or protease. Enfuvirtide is the first fusion inhibitor approved by the US Food and Drug Administration for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced patients.. This paper describes the pharmacologic properties and clinical usefulness of enfuvirtide.. Relevant information was identified through searches of MEDLINE (1990 to October 2003), International Pharmaceutical Abstracts (1970 to October 2003), and meeting abstracts of major HIV/AIDS conferences (1996-2003) using the search terms enfuvirtide, pentafuside, T-20, DP-178, and fusion inhibitor.. In vitro, enfuvirtide exhibits activity against HIV-1 isolates that are resistant to all other classes of anti-retroviral medications. Enfuvirtide blocks the entry of HIV-1 into host cells by interfering with virus-cell fusion, making it unique among licensed antiretroviral medications. In human adults, enfuvirtide has a volume of distribution of 5.48 L, is highly bound to plasma protein (92%), has a plasma elimination half-life of 3.8 hours, and is catabolized by peptidases and proteinases in various tissues. Dose adjustment does not appear necessary on the basis of age, race, or body weight, but may be warranted in women weighing <50 kg. A literature review did not identify any data on the disposition of enfuvirtide in patients with hepatic or renal insufficiency. Clinical trials suggest that enfuvirtide reduces plasma HIV-1 RNA levels in highly treatment-experienced patients taking an optimized antiretroviral regimen. Pivotal trials indicated a mean change in HIV-1 RNA of -1.48 log(10) copies/mL in the enfuvirtide arm at week 48, compared with -0.63 log(10) copy/mL in the control arm ( P<0.001 ). The mean absolute increase on CD4 cell count was 46 cells/mm(3) (91 cells/mm(3)) in the enfuvirtide arm vs 45 cells/mm(3) in the control arm; P<0.001 ). The most commonly reported (>15 cases per 100 patient-years of exposure) adverse events (AEs) in clinical trials included injection-site reactions, diarrhea, nausea, fatigue, insomnia, peripheral neuropathy, headache, vomiting, and fever. The most commonly reported (> or =2%) laboratory abnormalities (grade III or IV) were eosinophilia, anemia, and increases in amylase, lipase, triglycerides, creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase. In clinical trials, serious AEs leading to study discontinuation occurred in 12.9% ( 114/885 ) of patients in the enfuvirtide arm, compared with 10.7% ( 12/112 ) in the control arm ( P = NS ). The recommended dosage of enfuvirtide is 90 mg SC BID in adults and 2 mg/kg SC BID in children. Efficacy studies in children are ongoing.. Although additional studies are needed, enfuvirtide appears to be a promising agent, in combination with other antiretroviral agents, for the treatment of HIV infection in treatment-experienced patients.

Topics: Clinical Trials as Topic; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; Economics, Pharmaceutical; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments

Enfuvirtide (Fuzeon, T-20), jointly developed by Trimeris Inc. and Roche Pharmaceuticals, is the first of a new class of antiretroviral agents called fusion inhibitors that block HIV-1 entry into the host cell by binding to the gp41 subunit of the HIV-1 envelope glycoprotein. In vitro and in vivo studies have demonstrated potent antiretroviral activity among HIV-positive patients, including those with multi-drug resistant virus. The pharmacokinetic profile of subcutaneously administered enfuvirtide allows for twice-daily administration, although the possibility of once-daily dosing has not been excluded. Phase II and III clinical studies conducted to date have confirmed that enfuvirtide is an effective and safe drug for treating both adult and pediatric HIV-1-positive patients, with only mild or moderate adverse effects being reported.

Topics: Animals; Clinical Trials as Topic; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments

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.

Topics: Amino Acid Motifs; Animals; Anti-HIV Agents; CCR5 Receptor Antagonists; CD4 Antigens; Clinical Trials as Topic; Cyclic N-Oxides; Dogs; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; Haplorhini; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Membrane Fusion; Membrane Glycoproteins; Organic Chemicals; Oximes; Peptide Fragments; Piperazines; Piperidines; Protein Binding; Pyridines; Pyrimidines; Rabbits; Receptors, CCR5; Receptors, CXCR4; Reverse Transcriptase Inhibitors; Spiro Compounds

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.

Topics: Clinical Trials, Phase III as Topic; Drug Hypersensitivity; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections, Intradermal; Patient Education as Topic; Peptide Fragments; Pneumonia; Randomized Controlled Trials as Topic; Treatment Outcome

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

This review surveys the different classes of drugs.. We searched electronic databases and selected articles about pharmacotherapy with anti-retroviral drugs.. We discuss anti-retroviral drugs: the nucleotide reverse transcriptase inhibitors (NRTIs), the non-nucleoside reverse transcriptase inhibitors (NNRTIs), and the protease inhibitors (PIs). The combination of a PI and two NRTIs is very effective and lowers the viral load to below the limit of detection. However, it is not yet possible to eliminate the virus completely. Recently, the first member of a brand new class of drugs has become available, the fusion inhibitor enfuvirtide. We also discuss the problems associated with combining anti-retroviral drugs, such as compliance, resistance and serious side effects.. It is important to investigate new combinations with new classes of drugs, like the fusion inhibitors, for better effectiveness and fewer side effects.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV Protease Inhibitors; Humans; Patient Compliance; Peptide Fragments; Reverse Transcriptase Inhibitors

Fusion inhibitors are a new class of antiretroviral drugs (ARVs) for the treatment of human immunodeficiency virus infection. Enfuvirtide is the first in this class to reach market approval. Fusion inhibitors block the last step in the three-step viral entry process consisting of attachment, co-receptor binding and fusion, thereby preventing viral capsid entry into the host cell. Enfuvirtide has a unique mechanism of action and high viral target specificity, and in clinical trials has been shown to exhibit both high efficacy and low toxicity. Enfuvirtide is a peptide mimetic of an essential region within viral envelope glycoprotein gp41 that functions by blocking gp41 structural rearrangements at a transitional pre-fusion conformation. Although different clinical isolates show variation in susceptibility to enfuvirtide, primary resistance has not been observed, and thus enfuvirtide-naive isolates remain clinically sensitive. Acquired resistance centres round a 10 amino acid motif between residues 36 and 45 in gp41 that forms part of the binding site of enfuvirtide. The 10 amino acid motif is critical for viral fusion, and enfuvirtide-resistant mutants show poor replicative capacity compared with wild type. Reversion to a wild-type, drug-sensitive state has been reported following enfuvirtide withdrawal.

Topics: Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Mutation; Peptide Fragments

The mechanism of action, pharmacokinetics, clinical efficacy, adverse effects, and availability of enfuvirtide are discussed.. To date, 20 antiretrovirals have been approved by FDA for the treatment of HIV infection. The recent approval of enfuvirtide offers a new and fourth class of antiretroviral agents called fusion inhibitors. Enfuvirtide is indicated for use in treatment-experienced patients who have evidence of viral replication despite receiving current therapy. The drug is a 36-amino-acid synthetic peptide that prevents completion of the HIV fusion sequence. Absolute bioavailability after subcutaneous injection is 84%. Clinical trials indicate that adding enfuvirtide to a salvage regimen in heavily treated patients may lead to an improved virologic response. Up to a 1.48 log decrease in the viral load was seen at 48 weeks when enfuvirtide was combined with an optimized background regimen. Patients who have at least two or more active drugs in the regimen, a CD4+ cell count of >100 cells/mm3, and previous exposure to two or more antiretrovirals prior to starting enfuvirtide appear to respond best. The most common adverse effect, occurring in 98% of all enfuvirtide recipients, is an injection-site reaction that generally can be managed nonpharmacologically. A much less common but more significant concern is an increased risk of bacterial pneumonia. Enfuvirtide is available through the Fuzeon Progressive Distribution Program. The annual cost of therapy is about 24,000 dollars.. Enfuvirtide is the first fusion inhibitor available for the treatment of HIV infection. The drug is indicated for use with other antiretroviral agents in treatment-experienced patients who have evidence of HIV replication despite ongoing antiretroviral treatment.

Topics: Drug Resistance; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Patient Compliance; Patient Education as Topic; Peptide Fragments; Treatment Outcome

Extraordinary advancements have been made over the past decade in our understanding of the molecular mechanism of human immunodeficiency virus (HIV) entry into cells. The external HIV envelope glycoprotein, gp120, sequentially interacts with two cellular receptor molecules, the CD4 glycoprotein and a chemokine receptor, such as CCR5 or CXCR4, leading to the activation of the fusogenic domain of the transmembrane viral glycoprotein, gp41, which changes its conformation to create a hairpin structure that eventually triggers fusion between the viral and cellular membranes. Each of these discrete steps in the viral entry process represents a potential target for new antiviral agents. Current efforts to develop safe and effective HlV entry inhibitors are focused on naturally occurring proteins (e.g., chemokines, antibodies), engineered or modified derivatives of natural proteins (e.g., multimerized soluble CD4, gp41--or chemokine--derived synthetic peptides), as well as small synthetic compounds obtained either by high-throughput screening of large compound libraries or by structure-guided rational design. The recent introduction in therapy of the first fusion inhibitor, the gp41-derived synthetic peptide T20, heralds a new era in the treatment of AIDS, which will hopefully lead to more effective multi-drug regimens with reduced adverse effects for the patients.

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; Receptors, CCR5; Receptors, Chemokine; Receptors, CXCR4

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.

Topics: Biological Availability; Dose-Response Relationship, Drug; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; Virus Replication

In combination with other antiretroviral drugs, enfuvirtide is indicated in the treatment of HIV-1 patients, exposed or with failure to previous therapy with at least one of each of the three antiretroviral drugs classes (nucleoside inhibitors, non nucleoside inhibitors and protease inhibitors) or intolerant to these therapies. Genotypic resistance tests are helpful to evaluate acquired resistance to individual drugs, to select the remaining active drugs and to eliminate from the background regimen those with characterized resistance. In patients receiving enfuvirtide plus an optimized background regimen, the best results are reported in those with a baseline CD4+ count above 100/mm3, a plasma viral load below 100000 copies/ml, having been previously treated with less than 10 antiretroviral drugs and having at least 2 active drugs in their background regimen. Patients combining these 4 criteria have an 80% chance to have a plasma viral load below 400 copies/ml after a 24 weeks course of therapy. In terms of Quality of Life, studies demonstrated that patients treated with enfuvirtide have improvement in many measures of health-related quality of life, comparatively to those receiving the optimized therapy alone.

Topics: Anti-Retroviral Agents; Drug Resistance; Drug Therapy, Combination; Enfuvirtide; Genotype; Health Status; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Quality of Life; Viral Load

Treatment-experienced patients with HIV may harbor virus that has accumulated several mutations conferring decreased susceptibility to one or more antiretroviral drugs. For clinicians treating these patients, identifying a tolerable antiretroviral regimen with a reasonable chance of a durable virologic effect represents a major challenge. The first priority is to identify and correct the mechanisms responsible for previous treatment failure. Resistance testing and drug level monitoring may be useful in this setting. The patient's history of antiretroviral drug tolerability, comorbidities, and concomitant medications should be considered. Patients embarking on multiple-drug regimens will require close monitoring for adherence, toxicities, and drug-drug interactions. The guiding principle when constructing a rescue or salvage regimen is to achieve a cumulative activity score greater than 2, recognizing that some agents will have only partial activity. Some new drugs are available that may be helpful if used carefully with an active background regimen.

Topics: Adenine; Anti-HIV Agents; Anti-Retroviral Agents; Atazanavir Sulfate; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Oligopeptides; Organophosphonates; Peptide Fragments; Pyridines; Pyrones; Randomized Controlled Trials as Topic; Sulfonamides; Tenofovir; Treatment Failure; Viral Load

To review the pharmacology, virology, pharmacokinetics, efficacy, safety, and clinical use of enfuvirtide.. English-language MEDLINE and AIDSline searches were performed (1966-January 2003) using enfuvirtide, T-20, gp41, and fusion inhibitors as key words. Abstracts from infectious diseases and HIV scientific meetings were identified.. All publications and meeting abstracts were reviewed and relevant items included. In vitro and preclinical studies were included, as well as Phase II and III clinical trials.. Enfuvirtide is a fusion inhibitor used for the treatment of HIV-1 infection. Given its unique mechanism of action, most HIV-1 isolates are susceptible to enfuvirtide. Enfuvirtide is administered by subcutaneous injection twice daily. In clinical trials with antiretroviral-experienced patients, enfuvirtide was effective at suppressing HIV-RNA and increasing CD4+ T-cell counts. Enfuvirtide should be used in combination with other active antiretroviral agents to optimize its efficacy and limit resistance. Injection site reactions associated with administration of the drug are experienced in the majority of patients. Availability of enfuvirtide may be limited by a complex manufacturing procedure.. Enfuvirtide is an effective treatment option for HIV-1-infected individuals when used in combination with other antiretroviral agents. It may be used as part of a regimen for treatment-experienced patients.

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Injections, Subcutaneous; Meta-Analysis as Topic; Peptide Fragments

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.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments

Enfuvirtide is the first of a new class of drugs, the fusion inhibitors. It is a synthetic peptide which binds to the HIV glycoprotein 41 (gp41), blocking fusion of the viral and cellular membranes. HIV isolates with reduced susceptibility to enfuvirtide have been recovered from patients receiving enfuvirtide in combination with other antiretroviral agents. Enfuvirtide 90mg (subcutaneously, twice daily) in combination with optimised background (OB) antiretroviral therapy significantly reduced plasma HIV RNA levels compared with OB alone after treatment for 24 weeks in two randomised trials involving adults with advanced HIV infection. The antiviral efficacy of enfuvirtide was maintained through to 48 weeks. At 24 and 48 weeks, the increase from baseline in the CD4+ cell count was significantly greater for patients receiving enfuvirtide plus OB than for those receiving OB alone. Enfuvirtide 30 mg/m(2) or 60 mg/m(2) in combination with other antiretroviral agents reduced plasma HIV RNA levels and increased CD4+ cell counts in a small trial involving paediatric patients with HIV infection. Local injection-site reactions were common. Lymphadenopathy and pneumonia occurred more often in patients receiving enfuvirtide plus OB than in the control group. The incidence of most other events was similar in each group.

Topics: Adolescent; Adult; Area Under Curve; Biological Availability; Cells, Cultured; Child; Cost-Benefit Analysis; Enfuvirtide; Half-Life; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic

With the number of people living with HIV infection increasing and the problems of drug resistance and long-term toxicity associated with current antiretroviral agents continuing, there is a growing need for new therapy options. Enfuvirtide is the first fusion inhibitor, a new class of drug, to be licensed for the treatment of HIV infection and is a welcome addition to the arsenal of antiretrovirals. This paper, which is the result of a multidisciplinary discussion meeting, reviews current practice in treating HIV infection, the clinical data available on enfuvirtide and discusses its introduction into clinical practice. Data available to date indicate that enfuvirtide is appropriate for use in patients who have previously taken nucleoside reverse transcriptase inhibitor (NRTI), non-NRTI and protease inhibitor containing regimens and are either intolerant of them or have experienced virological failure. Enfuvirtide should ideally be used while the patient still has other active drug options available to them to combine with enfuvirtide in an effective therapy regimen.

Topics: Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Patient Satisfaction; Patient Selection; Peptide Fragments; Treatment Outcome

Resistance-testing technology has been incorporated into the standard of care for human immunodeficiency virus type 1 (HIV-1) infection and therapy with protease and reverse transcriptase inhibitors. Inhibitors of HIV-1 entry represent an emerging mode of antiretroviral therapy, and HIV-1 entry inhibitors encompass three mechanistically distinct classes of agents known as attachment inhibitors, coreceptor inhibitors, and fusion inhibitors. Each class of agent has demonstrated promise in controlled clinical trials, and understanding the determinants and evolution of viral resistance will be critical for the optimal development and deployment of these new treatment classes. Advances in resistance-testing technologies have paralleled the development of HIV-1 entry inhibitor therapies, and the available data support the notion that attachment, coreceptor and fusion inhibitors offer complementary modes of therapy and distinct resistance profiles.

Topics: Amides; Anti-HIV Agents; Benzylamines; CD4 Immunoadhesins; Cyclams; Drug Resistance, Viral; Enfuvirtide; Heterocyclic Compounds; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Peptide Fragments; Piperazines; Quaternary Ammonium Compounds

Topics: Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; HIV-2; Humans; Peptide Fragments

Topics: Anti-HIV Agents; Benzylamines; CD4 Immunoadhesins; Cyclams; Enfuvirtide; Heterocyclic Compounds; HIV; HIV Envelope Protein gp41; HIV Infections; Humans; Membrane Fusion; Peptide Fragments; Receptors, HIV

In recent years, exciting developments in the understanding of the multi-step HIV-1 entry process have revealed potential approaches for therapeutic intervention that will compensate for the early disappointments of the soluble CD4 antigen approach. Although details of the HIV-1 fusion process are clearly complex, the proof-of-concept in the clinic provided by T-20 gives high hopes that new generation inhibitors of HIV fusion will be developed. This review highlights novel drug discovery technologies that are being employed in the search for such inhibitors.

Topics: Anti-HIV Agents; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Membrane Fusion; Peptide Fragments

Classical antiretroviral agents may acutely impact on metabolic, mitochondrial, renal and hepatic function in HIV-infected and uninfected persons. Fusion and integrase inhibitors are supposed to be safer, but have been scarcely investigated. To avoid any interference with HIV or other antiretrovirals, we assessed markers of these toxicities in healthy adult volunteers treated with Enfuvirtide (T20) or Raltegravir (RAL).. Twenty-six healthy participants were randomized to T20/90mg vs. placebo (n = 12) or RAL/400mg vs. placebo (n = 14) every 12h in two 7-day periods separated by a 4-week washout period. Major end-points were changes in lipid profile (total cholesterol, high-density-lipoprotein (HDL)-cholesterol, low-density-lipoprotein (LDL)-cholesterol, triglycerides), insulin resistance (glucose) and mitochondrial toxicity (mitochondrial DNA content-mtDNA-in peripheral blood mononuclear cells). Renal and hepatic toxicity (creatinine, alanine transaminase (AST), alanine aminotransferase (ALT), bilirubin and total plasma proteins) and overall safety were also analysed. Effect of period, treatment, and basal measures were evaluated for each end-point.. Neither T20-administration nor RAL-administration yielded to any statistic significant change in the markers of metabolic, mitochondrial, renal or hepatic toxicity assessed. No symptoms indicative of drug toxicity were neither found in any subject.. In absence of HIV infection, or concomitant treatment, short-term exposure to T20 or RAL in healthy adult volunteers did not lead to any indicative changes in toxicity markers thus presuming the safe profile of both drugs.

Topics: Adult; Alanine Transaminase; Anti-Retroviral Agents; Creatine; Enfuvirtide; Healthy Volunteers; HIV Infections; Humans; Insulin Resistance; Kidney; Leukocytes, Mononuclear; Lipids; Liver; Male; Metabolism; Mitochondria; Raltegravir Potassium

In the ANRS EASIER trial where treatment-experienced patients switched from enfuvirtide (ENF) to raltegravir (RAL), a high incidence of transaminase elevation was reported in the RAL arm.. We compared the incidence of emergent liver enzyme elevations (LEE) of grade 2 or more among patients randomized to the maintenance ENF arm or the switch RAL arm up to W24. We also assessed the overall incidence of LEE over the 48-week duration of the trial and baseline risk factors for grade 2 or more alanine aminotransferase (ALT) elevation using univariate and multivariate analyses.. During the first 24 weeks, 6/84 (7.1 %) and 2/85 patients (2.4 %) presented with ALT elevation of grade 2 or more in the RAL and ENF arms, respectively (p = 0.21). Grade 2 or more γGT and ALP elevations were seen in 18 and 11 % (p = 0.35), and 5 and 1 % (p = 0.14) of patients in the RAL and ENF arms, respectively. The 48-week incidence of grade 2 or more LEE was 11.6 per 100-pts-years for ALT, 24.5 per 100-pts-years for γ-GT and 4.5 per 100-pts-years for ALP, respectively. In the multivariate analysis, tipranavir/ritonavir use (OR 3.66; 95 % CI [1.20-11.1], p = 0.022) and elevated ALT at baseline (OR 10.3; 95 % CI [2.67-39.6], p < 10(-3)) were significantly associated with a grade 2 or more ALT elevation during follow-up.. The incidence of LEE was relatively high in these highly treatment-experienced patients switching to a RAL-based regimen. Both tipranavir/ritonavir use and high baseline ALT levels were associated with an increased risk of ALT.. ClinicalTrials.gov identifier: NCT00454337.

Topics: Adult; Alanine Transaminase; Chemical and Drug Induced Liver Injury; Drug Substitution; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; Humans; Incidence; Liver Function Tests; Male; Middle Aged; Peptide Fragments; Raltegravir Potassium; Risk Factors

Regimen selection for highly treatment-experienced patients is complicated.. Using a web-based utility, study team members reviewed antiretroviral (ARV) history and resistance data and recommended individual ARV regimens and nucleoside reverse transcriptase inhibitor (NRTI) options for treatment-experienced participants consisting of 3-4 of the following agents: raltegravir (RAL), darunavir (DRV)/ritonavir, tipranavir (TPV)/ritonavir, etravirine (ETR), maraviroc (MVC), and enfuvirtide (ENF). We evaluated team recommendations and site selection of regimen and NRTIs. Associations between baseline factors and the selection of a complex regimen (defined as including four ARV agents or ENF) were explored with logistic regression.. A total of 413 participants entered the study. Participants initiated the first or second recommended regimen 86% of the time and 21% of participants started a complex regimen. In a multivariable model, ARV resistance to NRTI (odds ratio [OR] = 2.2), non-nucleoside reverse transcriptase inhibitor (NNRTI, OR = 6.2) or boosted protease inhibitor (PI, OR = 6.6), prior use of integrase strand transfer inhibitor (INSTI, OR = 25), and race-ethnicity (all P ≤ 0.01) were associated with selection of a complex regimen. Black non-Hispanic (OR = 0.5) and Hispanic participants from the continental US (OR = 0.2) were less likely to start a complex regimen, compared to white non-Hispanics.. In this multi-center trial, we developed a web-based utility that facilitated treatment recommendations for highly treatment-experienced patients. Drug resistance, prior INSTI use, and race-ethnicity were key factors in decisions to select a more complex regimen.

Topics: Adult; Anti-HIV Agents; Anti-Retroviral Agents; Darunavir; Drug Resistance, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; Humans; Male; Middle Aged; Nitriles; Peptide Fragments; Pyridazines; Pyrimidines; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Salvage Therapy

Topics: Anti-HIV Agents; Enfuvirtide; Genotype; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Peptide Fragments; Randomized Controlled Trials as Topic; Treatment Outcome; Viral Tropism

The pharmacokinetics assessment in two clinical studies of sifuvirtide (a novel HIV fusion inhibitor) was first reported in Chinese HIV patients. Nineteen treatment-naive HIV patients were treated with s.c.(subcutaneous injection) sifuvirtide [10 or 20 mg q.d.(quaque die)] for 28 days in study 1, and eight treatment-experienced HIV patients were treated with s.c. sifuvirtide (20 mg q.d.) in combination with HAART drugs (lamivudine, didanosine, and Kaletra) for 168 days in study 2. In study 1, T1/2 was 17.8 ± 3.7 h for 10 mg group and 39.0 ± 3.5 h for 20 mg group; the mean Cmax of last dose was 498 ± 54 ng/mL for 10 mg group and 897 ± 136 ng/mL for 20 mg group. In study 2, T1/2 was 6.71 ± 2.17 h in treatment-experienced patients. Cmax was 765 ± 288 ng/mL after last 168th dosage. Sifuvirtide showed improved clinical pharmacokinetics characteristics compared with Enfuvirtide, and showed very different pharmacokinetic characteristics between treatment-naive and treatment-experienced patients. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:4038-4047, 2014.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Double-Blind Method; Drug Combinations; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Peptide Fragments; Peptides; Ritonavir

In HIV-1-infected patients receiving antiretroviral therapy (ART), the relationship between residual viraemia and ex vivo recovery of infectious virus from latently infected CD4 cells is uncertain.. We measured residual viraemia (HIV-1 RNA copies/ml) by single-copy assay (SCA) and the latent reservoir by infectious virus recovery from resting memory CD4 cells (infectious units per million cells [IUPM]) in patients who initiated ART. We assessed immune activation by measuring CD38 expression on T-cells.. Ten patients who initiated ART and maintained a plasma HIV-1 RNA level < 200 copies/ml had residual viraemia and IUPM measured every 24 weeks. Five of 10 patients had longitudinal IUPM measured at weeks 24-96; the remainder had IUPM measured 1-3 times over 24-72 weeks. Analyses of 29 paired measurements revealed a positive association between level of residual viraemia and IUPM (0.56 higher log10 HIV-1 RNA copies/ml per 1 log10 higher IUPM; P = 0.005). Residual viraemia level was positively associated with CD38 density and percentage on CD8+ T-cells in concurrent samples and with pre-ART HIV-1 RNA levels.. In patients with HIV-1 RNA levels < 200 copies/ml 24-96 weeks after initiating ART, the level of viraemia is positively associated with infectious virus recovery from resting memory CD4 cells. Whether this association persists after longer-term suppressive ART needs to be determined. If additional studies show that residual viraemia measured by SCA reflects the size of the latent reservoir in patients who have had virological suppression for longer periods of time, this could facilitate testing of potentially curative strategies to reduce this important reservoir.

Topics: ADP-ribosyl Cyclase 1; Anti-HIV Agents; CD4-Positive T-Lymphocytes; Enfuvirtide; Gene Expression; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Immunologic Memory; Peptide Fragments; RNA, Viral; Viral Load; Viremia

Stored plasma specimens from 164 participants in the ANRS 138 trial were analyzed to determine interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and D-dimer levels at baseline and weeks 24 and 48. These virologically suppressed, treatment-experienced patients were randomly assigned to undergo an immediate switch (IS) or a deferred switch (DS; at week 24) from an enfuvirtide-based antiretroviral therapy (ART) regimen to a raltegravir-based regimen. At week 24, a significant decrease from baseline was observed in the IS arm, compared with the DS arm, for IL-6 level (-30% vs +10%; P < .002), hsCRP level (-46% vs +15%; P < .0001), and D-dimer level (-40% vs +6%; P < .0001). At week 48, there was a reproducible decrease in levels of all biomarkers in the DS arm.

Topics: Adult; Anti-HIV Agents; Biomarkers; Blood Coagulation; C-Reactive Protein; CD4 Lymphocyte Count; Enfuvirtide; Female; Fibrin Fibrinogen Degradation Products; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Specimen Handling; Viral Load

The aims of the study were to assess in patients with advanced HIV disease receiving antiretroviral therapy (ART) intensification with enfuvirtide (i) resistance at virological failure (VF), (ii) impact of baseline tropism on immunovirological response, and (iii) HIV-1 DNA tropism evolution during ART.. The ANRS 130 APOLLO randomized trial evaluated in naive patients the immunovirological impact of standard ART without (control arm) or with enfuvirtide. Tropism was determined on RNA and DNA by V3-loop sequencing interpreted using the Geno2Pheno algorithm.. At baseline the median CD4 cell count was 30 cells/mm(3). Among the 170 patients assessable in this virological substudy, HIV-1 RNA tropism was as follows: 60% of viruses were R5 and 40% were R5X4/X4. HIV-1 DNA tropism was as follows: 54% were R5 and 46% were R5X4/X4. At week 24, 39% and 49% of patients experienced VF in the enfuvirtide and control arms, respectively. In the enfuvirtide arm, only resistance-associated mutations to enfuvirtide were detected. In the control arm, two patients displayed drug-resistant viruses at the time of VF. No impact of baseline tropism was observed on immunovirological response, regardless of the study arm. Among the 25 patients experiencing DNA tropism switch between baseline and week 24, 16 (64%) switched from R5 to R5X4/X4. These latter were mostly successfully suppressed patients receiving enfuvirtide and exhibiting poorer immunological response.. Baseline RNA tropism had no impact on the immunovirological response. Drug resistance mutations were only detected for the fusion inhibitor. Finally, the mechanism of replenishment of the viral cellular reservoir with X4 viruses observed needs to be further analysed.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Enfuvirtide; Evolution, Molecular; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Middle Aged; Mutation, Missense; Peptide Fragments; Viral Tropism; Young Adult

We studied whether addition of enfuvirtide (ENF) to a background combination antiretroviral therapy (cART) would improve the CD4 cell count response at week 24 in naive patients with advanced HIV disease. ANRS 130 Apollo is a randomized study, conducted in naive HIV-1-infected patients, either asymptomatic with CD4 counts of <100/mm(3) or stage B/C disease with CD4 counts of <200/mm(3). Patients received tenofovir-emtricitabine with lopinavir-ritonavir (LPV/r) or efavirenz and were randomized to receive ENF for 24 weeks (ENF arm) or not (control arm). The primary endpoint was the proportion of patients with CD4 counts of ≥ 200/mm(3) at week 24. A total of 195 patients were randomized: 73% had stage C disease, 78% were male, the mean age was 44 years, the median CD4 count was 30/mm(3), and the median HIV-1 RNA load was 5.4 log(10) copies/ml. Eighty-one percent of patients received LPV/r. One patient was lost to follow-up, and eight discontinued the study (four in each arm). The proportions of patients with CD4 counts of ≥ 200/mm(3) at week 24 were 34% and 38% in the ENF and control arms, respectively (P = 0.53). The proportions of patients with HIV-1 RNA loads of <50 copies/ml were 74% and 58% at week 24 in the ENF and control arms, respectively (P < 0.02), and the proportion reached 79% in both arms at week 48. Twenty (20%) and 12 patients (13%) in the ENF and control arms, respectively, experienced at least one AIDS event during follow-up (P = 0.17). Although inducing a more rapid virological response, addition of ENF to a standard cART does not improve the immunological outcome in naive HIV-infected patients with severe immunosuppression.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cyclopropanes; Deoxycytidine; Drug Combinations; Emtricitabine; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Immune Tolerance; Lopinavir; Male; Organophosphonates; Peptide Fragments; Ritonavir; RNA, Viral; Tenofovir; Treatment Outcome; Viral Load

To evaluate whether the addition of enfuvirtide to standard highly active antiretroviral therapy (HAART) could confer immunovirological benefits in human immunodeficiency virus (HIV)-infected very late presenters. The current study is an open comparative therapeutic trial of standard protease inhibitor (PI)-based HAART ± additional enfuvirtide in treatment-naïve deeply immunologically impaired HIV-positive patients.. Very late presenters (CD4 <50/mm(3)), without tuberculosis and neoplasms, were alternatively allocated to two nucleoside reverse transcriptase inhibitors (NRTIs) and lopinavir/ritonavir without (control arm, CO) or with (ENF arm) enfuvirtide 90 mg bid. Enfuvirtide was administered until the achievement of viral load <50 copies/ml and for at least 24 weeks. The primary objective was the magnitude of CD4+ cell recovery at 6 months. HIV RNA was intensively monitored in the first month, and, thereafter, monthly, as for CD4+ cell count and percentage, clinical data, and plasma drug concentrations.. Of 22 enrolled patients (11 per arm), 19 completed the study (10 in the ENF arm). Baseline CD4+ cell counts and % were comparable, with 20 CD4+/mm(3) (12-37) and a percentage of 3.3 (1.7-7.1) in the ENF arm, and 16 CD4+/mm(3) (9-29) and a percentage of 3.1 (2.3-3.8) in the CO arm, respectively. The baseline viral load was also comparable between the two arms, with 5.77 log10 (5.42-6) and 5.39 log10 (5.06-6) in the ENF and CO arms, respectively. Enfuvirtide recipients had higher CD4+ percentage at week 8 (7.6 vs. 3.6%, p = 0.02) and at week 24 (10.7 vs. 5.9%, p = 0.02), and a greater CD4+ increase at week 24 (207 vs. 134 cells/mm(3), p = 0.04), with 70% of enfuvirtide intakers versus 12.5% of controls who achieved a CD4+ cell count >200/mm(3) (p = 0.01). At 48 weeks, patients in the ENF arm had CD4+ cell counts higher than controls (251 vs. 153cells/mm(3), p = 0.04) and were also found to be faster in reaching a CD4 cell count over 200/mm(3): 18 (8-24) versus 48 (36-108) weeks (p = 0.01). Viral load decay at week 4 was greater in the ENF arm (-3 vs. -2.2 log, p = 0.04), while the proportion of patients with viral load <50 copies/ml at week 24 was comparable.. In this pilot study, the addition of enfuvirtide to a lopinavir-based HAART was shown to be associated with a significantly faster and greater immunological recovery in newly discovered HIV-positive patients with very low CD4+ cell counts. Induction strategies using an enfuvirtide-based approach in such subjects warrant further investigation.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Enfuvirtide; Female; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Italy; Male; Middle Aged; Peptide Fragments; Pilot Projects; Reverse Transcriptase Inhibitors; Viral Load

We previously described an HIV-1-infected individual who developed resistance to vicriviroc (VCV), an investigational CCR5 antagonist, during 28 weeks of therapy (Tsibris AM et al., J. Virol. 82:8210-8214, 2008). To investigate the decay of VCV resistance mutations, a standard clonal analysis of full-length env (gp160) was performed on plasma HIV-1 samples obtained at week 28 (the time of VCV discontinuation) and at three subsequent time points (weeks 30, 42, and 48). During 132 days, VCV-resistant HIV-1 was replaced by VCV-sensitive viruses whose V3 loop sequences differed from the dominant pretreatment forms. A deep-sequencing analysis showed that the week 48 VCV-sensitive V3 loop form emerged from a preexisting viral variant. Enfuvirtide was added to the antiretroviral regimen at week 30; by week 48, enfuvirtide treatment selected for either the G36D or N43D HR-1 mutation. Growth competition experiments demonstrated that viruses incorporating the dominant week 28 VCV-resistant env were less fit than week 0 viruses in the absence of VCV but more fit than week 48 viruses. This week 48 fitness deficit persisted when G36D was corrected by either site-directed mutagenesis or week 48 gp41 domain swapping. The correction of N43D, in contrast, restored fitness relative to that of week 28, but not week 0, viruses. Virus entry kinetics correlated with observed fitness differences; the slower entry of enfuvirtide-resistant viruses corrected to wild-type rates in the presence of enfuvirtide. These findings suggest that while VCV and enfuvirtide select for resistance mutations in only one env subunit, gp120 and gp41 coevolve to maximize viral fitness under sequential drug selection pressures.

Topics: Anti-HIV Agents; Cell Line; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation; Peptide Fragments; Phylogeny; Piperazines; Pyrimidines; Virus Internalization; Virus Replication

The objective of the present study was to evaluate the virological efficacy of a 3-month short-course intensification with enfuvirtide (ENF) associated with an optimized background regimen (OBR) in treatment-experienced patients infected with HIV-1 with multiple therapeutic failures. This was a prospective, randomized, open-label multicenter trial including patients infected with HIV-1 and harboring a multi-resistant virus that was still susceptible to at least 2 active compounds. Patients were randomized (1:1) to receive OBR + ENF or OBR alone. ENF was discontinued at Week 12. The primary endpoint was the proportion of patients with plasma viral load <50 copies/ml at Week 24. Fifteen patients were randomized into the OBR group and 14 into the OBR + ENF group with a median viral load of 4.1 log(10)  copies/ml and a median CD4+ cell count of 346 cells/mm(3) . The primary endpoint was achieved in 93% (14/15) and 79% (11/14) of patients, respectively. Eighty-seven percent (13/15) of patients had a viral load <50 copies/ml as soon as Week 12 in the OBR group and 79% (11/14) in the OBR + ENF group. At Week 12, the median CD4+ cell count was 327 in the OBR and 437 in the OBR + ENF groups and at Week 24 they were comparable. Intensification with ENF had no significant impact on PBMCs HIV-DNA levels. A 3-month short-course intensified treatment with ENF did not improve Week-24 virological response in treatment-experienced patients infected with HIV-1 harboring resistant viruses that were still susceptible to two antiretroviral drugs.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Prospective Studies; Salvage Therapy; Treatment Outcome; Viral Load

The aim of the study was to compare the metabolic and morphological effects of enfuvirtide plus an optimized background (OB) regimen vs. OB alone (control group) in treatment-experienced patients in the T-20 vs. Optimized Regimen Only (TORO) studies.. Body composition and metabolic changes were investigated in patients over 48 weeks, based on fasting chemistries, body weight, and other anthropometric measurements. Dual-energy X-ray absorptiometry (DEXA) and computed tomography (CT) scans were performed in a patient subgroup (n=155) at baseline and at weeks 24 and 48.. At week 48, mean changes from baseline were similar between treatment groups for glucose, insulin, C-peptide, total cholesterol, low-density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels. The enfuvirtide group experienced a significant increase in body weight [mean change from baseline +0.99 kg; 95% confidence interval (CI) +0.54, +1.44] and, in those who had body scans, there was a significant increase in truncal fat (by DEXA: median change +419.4 g; 95% CI+71.3, +767.5) and total fat [visceral adipose tissue (VAT)+subcutaneous adipose tissue (SAT) by single-slice abdominal CT scan: median change +25.5 cm(2) ; 95% CI+8.9, +42.0] over 48 weeks; significant increases in these parameters were not seen in the control group. There was no significant change in truncal:peripheral fat ratio in either the enfuvirtide or the control group.. The addition of enfuvirtide to an OB regimen does not appear to have unfavourable effects on fat distribution or metabolic parameters.

Topics: Absorptiometry, Photon; Adolescent; Adult; Aged; Aged, 80 and over; Antiretroviral Therapy, Highly Active; Body Composition; Body Weight; Dyslipidemias; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Middle Aged; Peptide Fragments; Tomography, X-Ray Computed; Waist Circumference; Waist-Hip Ratio; Young Adult

To assess safety and tolerability of enfuvirtide, an antiretroviral, in Thai patients with advanced HIV-1 disease who have received antiretroviral treatment and failed on regimens that contain at least one of each antiretroviral (ARV) classes (PIs, NRTIs, and NNRTIs), or who have intolerance to previous antiretroviral regimens.. An open-label non-comparative study of enfuvirtide used in salvage regimens along with the backbone antiretroviral therapy of choice in Thai HIV-1 experienced cases that have been treated with at least one of each available ARV classes.. Twenty-three patients were recruited from five participating centers. Seventeen patients (74%) completed 96 weeks of the treatment. Six patients prematurely withdrew from the present study in which three expired from HIV related complications, two withdrew consents, and one from adverse event. The most common adverse event is injection site reactions, which occurred in 22 patients. The manifestations and intensity varied from rash, erythema, edema, pain, induration, and bleeding at the injection sites, to inflammatory nodules. Most of the patients tolerated the treatment well. Enfuvirtide administered along with other antiretroviral combination provided a good control of the disease.. Enfuvirtide was well tolerated by Thai patients who participated in the present study. The adverse events did not compromise the patient compliance.

Topics: Adult; Anti-HIV Agents; Asian People; CD4 Lymphocyte Count; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Salvage Therapy; Thailand; Treatment Failure; Treatment Outcome; Young Adult

To assess the sustainable efficacy and safety of a switch from enfuvirtide to raltegravir in patients with multidrug-resistant HIV infection.. One hundred and seventy patients with multidrug-resistant HIV infection and suppressed plasma HIV RNA levels < 400 copies/mL under an enfuvirtide-based regimen were randomized to maintain their regimen or to switch to a raltegravir-based regimen (immediate group) in a 48 week prospective, randomized, open-label trial. At week 24, patients in the maintenance arm also switched to raltegravir (deferred group). Baseline genotypic susceptibility scores (GSSs) were calculated using available historical resistance tests. Efficacy was assessed by the cumulative proportion of patients with virological failure, defined as a confirmed plasma HIV RNA ≥ 400 copies/mL up to week 48. The EASIER ANRS 138 trial is registered at ClinicalTrials.gov (NCT00454337).. At baseline, 86% of patients had plasma HIV RNA levels <50 copies/mL and 86% had a GSS ≥ 1. Through to week 48, in the on-treatment analysis, only one patient in the immediate group, with a GSS of 0, developed virological failure. At week 48, 90% of patients in both the immediate and deferred groups had plasma HIV-1 RNA levels <50 copies/mL. Median CD4 cell counts remained stable during follow-up. Of note, 12 of 66 (18.2%) patients receiving a regimen combining raltegravir and ritonavir-boosted tipranavir experienced alanine aminotransferase elevations, which led to a switch from tipranavir to darunavir in 8 cases, without discontinuation of raltegravir.. In well-suppressed patients with multidrug-resistant HIV infection, a switch from enfuvirtide to raltegravir is generally well tolerated and has sustained antiviral efficacy when combined with a potent background regimen.

Topics: Adult; Alanine Transaminase; CD4 Lymphocyte Count; Drug Resistance, Multiple, Viral; Endpoint Determination; Enfuvirtide; Female; France; Genotype; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Peptide Fragments; Pilot Projects; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome

Progressive multifocal leukoencephalopathy (PML), a rare devastating demyelinating disease caused by the polyomavirus JC (JCV), occurs in severely immunocompromised patients, most of whom have advanced-stage HIV infection. Despite combination antiretroviral therapy (cART), 50% of patients die within 6 months of PML onset. We conducted a multicenter, open-label pilot trial evaluating the survival benefit of a five-drug cART designed to accelerate HIV replication decay and JCV-specific immune recovery.. All the patients received an optimized cART with three or more drugs for 12 months, plus the fusion inhibitor enfuvirtide during the first 6 months. The main endpoint was the one-year survival rate. A total of 28 patients were enrolled. At entry, median CD4+ T-cell count was 53 per microliter and 86% of patients had detectable plasma HIV RNA and CSF JCV DNA levels. Seven patients died, all before month 4. The one-year survival estimate was 0.75 (95% confidence interval, 0.61 to 0.93). At month 6, JCV DNA was undetectable in the CSF of 81% of survivors. At month 12, 81% of patients had undetectable plasma HIV RNA, and the median CD4+ T-cell increment was 105 per microliter. In univariate analysis, higher total and naive CD4+ T-cell counts and lower CSF JCV DNA level at baseline were associated with better survival. JCV-specific functional memory CD4+ T-cell responses, based on a proliferation assay, were detected in 4% of patients at baseline and 43% at M12 (P = 0.008).. The early use of five-drug cART after PML diagnosis appears to improve survival. This is associated with recovery of anti-JCV T-cell responses and JCV clearance from CSF. A low CD4+ T-cell count (particularly naive subset) and high JCV DNA copies in CSF at PML diagnosis appear to be risk factors for death.. ClinicalTrials.gov NCT00120367.

Topics: Adult; Anti-Retroviral Agents; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Male; Middle Aged; Peptide Fragments; Polymerase Chain Reaction

Human immunodeficiency virus type 1 (HIV-1) persists in a latent reservoir of infected resting memory CD4 cells in patients receiving antiretroviral therapy. We assessed whether multitarget therapy with enfuvirtide, 2 reverse-transcriptase inhibitors, and a ritonavir-boosted protease inhibitor leads to decay of this reservoir. Nineteen treatment-naive patients initiated this regimen; 9 experienced virologic suppression and continued enfuvirtide-containing therapy for at least 48 weeks. In enfuvirtide-treated patients with virological suppression, there was no decay of the latent reservoir (95% confidence interval for half-life, 11 months to infinity). The stability of the latent reservoir despite intensive therapy suggests that new strategies are needed to eradicate HIV-1 from this reservoir. (ClinicalTrials.gov identifier: NCT00051831 .).

Topics: Adult; Antiviral Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Peptide Fragments; Viral Load; Virus Latency

Human immunodeficiency virus (HIV) infection that persists despite antiretroviral therapy (ART) is a daunting problem. Given the limited evidence that resting CD4+ T cell infection (RCI) is affected by the histone deacetylase (HDAC) inhibitor valproic acid (VPA), we measured the stability of RCI and residual viremia in patients who added VPA with or without raltegravir (RAL), or enfuvirtide (ENF) with or without VPA, to standard ART.. Patients with plasma HIV RNA<50 c/mL added sustained-release VPA (Depakote ER) twice daily, RAL 400 mg twice daily, or ENF 90 mcg twice daily. Change in RCI was measured by outgrowth assays. Low-level viremia was quantitated by single-copy plasma HIV RNA assay (SCA).. In three patients on standard ART a depletion of RCI was observed after 16 weeks of VPA, but this effect waned over up to 96 weeks of further VPA. In two patients ENF added to stable ART had no effect on RCI. Simultaneous intensification with ENF and addition of VPA had no effect on RCI frequency in one patient, and resulted in a 46% decline in a second. No significant depletion of RCI (>50%) was seen in six volunteers after the addition of RAL and VPA. In 4 of the 6 patients this lack of effect might be attributed to intermittent viremia, low VPA levels, or intermittent study therapy adherence. Overall, there was no effect of the addition of RAL or ENF on low-level viremia measured by SCA.. The prospective addition of VPA and RAL, VPA and ENF, or ENF failed to progressively reduce the frequency of RCI, or ablate intermittent and low-level viremia. New approaches such as more potent HDAC inhibition, alone or in combination with intensified ART or other agents that may disrupt proviral latency must be pursued.

Topics: Antiretroviral Therapy, Highly Active; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; Drug Administration Schedule; Drug Therapy, Combination; Enfuvirtide; Enzyme Inhibitors; Histone Deacetylase Inhibitors; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Peptide Fragments; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Valproic Acid; Viremia

Antiretroviral treatment (ART) significantly reduces cerebrospinal fluid (CSF) HIV-1 RNA levels and residual viremia is less frequently found in CSF than in blood. However, persistent intrathecal immunoactivation is common, even after several years of ART. To investigate whether low-level CSF viremia and residual immunoactivation within the central nervous system (CNS) derive from ongoing local viral replication, we conducted a study of treatment intensification in patients on effective ART.. Ten patients on ART with plasma HIV RNA <50 copies per milliliter for >18 months were included. Intensification was given for in total 8 weeks: 4 weeks with maraviroc or lopinavir/ritonavir (good CNS penetration), and 4 weeks with enfuvirtide (poor CNS penetration). Lumbar punctures were performed 4 weeks before, at intensification commencement, at switchover after 4 weeks, at the conclusion of, and 4 weeks after the intensification period.. No significant changes in HIV RNA, neopterin, β2-microglobulin, immunoglobulin G index, albumin ratio, and CD4(+) T-cell count were observed, either in CSF or blood, neither before, during, nor after the intensification periods.. ART intensification did not reduce residual CSF HIV RNA levels or intrathecal immunoactivation in patients on ART. These findings do not support an ongoing viral replication in CNS.

Topics: Adult; Albumins; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Central Nervous System Infections; Cross-Over Studies; Cyclohexanes; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Immunoglobulin G; Lopinavir; Male; Maraviroc; Middle Aged; Neopterin; Peptide Fragments; Polymerase Chain Reaction; Ritonavir; RNA, Viral; Triazoles; Viral Load; Viremia; Virus Replication

Durable efficacy and long-term safety of antiretroviral therapy are important goals in the management of treatment-experienced patients. The 96-week efficacy and safety of the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine were evaluated in the Phase III DUET trials.. HIV type-1-infected treatment-experienced adults with viral loads >5,000 copies/ml and NNRTI and protease inhibitor resistance were randomized to receive etravirine 200 mg or placebo, each twice daily and in combination with a background regimen of darunavir/ritonavir twice daily, nucleoside/nucleotide reverse transcriptase inhibitors and optional enfuvirtide. The primary end point was the proportion of patients with viral load <50 copies/ml (intent-to-treat analysis, time-to-loss of virological response algorithm) at week 24. Results from both trials were combined in the pre-specified pooled 96-week analysis.. In total, 599 patients received etravirine and 604 received placebo. At week 96, 57% of patients in the etravirine group versus 36% in the placebo group had a viral load <50 copies/ml (P<0.0001); 91% and 88% of patients, respectively, had maintained this response from week 48. Mean increases in CD4(+) T-cell count from baseline at week 96 were 128 cells/mm(3) with etravirine versus 86 cells/mm(3) with placebo (P<0.0001). With the exception of rash, which was reported more frequently with etravirine than placebo (21% versus 12%, respectively; P<0.0001), the safety and tolerability profile of etravirine was similar to placebo over the treatment period.. Etravirine, in combination with an antiretroviral background regimen, provided durable virological and immunological responses with no new safety concerns in treatment-experienced patients over 96 weeks in the DUET trials.

Topics: Adult; Anti-HIV Agents; Darunavir; Double-Blind Method; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Nitriles; Peptide Fragments; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load

Treatment options for HIV-infected patients can be limited due to viral drug resistance to antiretroviral agents. Enfuvirtide (ENF) is an injectable entry/fusion inhibitor that is effective in achieving viral suppression when used in combination with protease inhibitors (PIs) in patients with pre-existing resistance. However, ENF treatment is associated with injection site reactions and dosing fatigue. This multicenter, open-label, Phase IIIb, 48-week pilot study assessed safety, tolerability, and effectiveness of the PI darunavir (DRV), boosted with ritonavir (DRV/r), and the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (ETR), when substituted for ENF/PI (±NNRTI)-based therapy. Ten virologically suppressed (HIV RNA less than 50 copies/ml) men who were intolerant to ENF were enrolled. Median (range) CD4+ count was 301 (187-663) cells/mm(3). Two patients discontinued the study; all remaining patients maintained a viral load of less than 50 copies/ml at Week 48. Viral load increased to greater than 50 copies/ml in two patients, but was eventually re-suppressed without the need for changes in treatment. Median (range) increase (last observation carried forward) in CD4+ count from baseline to Week 48 was 64 (-53-100) cells/mm(3). Two grade 3 adverse events (AEs), nausea and weight loss, and one serious AE, acute cholecystitis, were reported; each AE resolved without treatment interruption. Most common AEs related to study drug were fatigue, rash, headache, and diarrhea. Decreases in triglycerides, low-density lipoprotein, and high-density lipoprotein, were observed. This study suggests that a DRV/r- and ETR-based regimen can be substituted for an ENF-based regimen while maintaining virologic suppression.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Darunavir; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV Protease; HIV Reverse Transcriptase; Humans; Male; Middle Aged; Nitriles; Peptide Fragments; Pilot Projects; Pyridazines; Pyrimidines; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load

Ibalizumab (formerly TNX-355) is a humanized monoclonal antibody that binds CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1), and inhibits the viral entry process. A phase lb multidose study of the safety, pharmacokinetics, and antiviral activity of ibalizumab was conducted with 22 HIV-1-infected patients. Nineteen patients were randomized to receive either 10 mg/kg of body weight weekly (arm A) or a 10-mg/kg loading dose followed by 6 mg/kg every 2 weeks (arm B) intravenously for 9 weeks. Three patients were assigned to receive 25 mg/kg every 2 weeks for five doses (arm C). During the study, the patients remained off other antiretrovirals or continued a stable failing regimen. Treatment with ibalizumab resulted in substantial reductions in HIV-1 RNA levels (0.5 to 1.7 log(10)) in 20 of 22 subjects. In most patients, HIV-1 RNA fell to nadir levels after 1 to 2 weeks of treatment and then returned to baseline despite continued treatment. Baseline viral isolates were susceptible to ibalizumab in vitro, regardless of coreceptor tropism. Emerging resistance to ibalizumab was manifested by reduced maximal percent inhibition in a single-cycle HIV infectivity assay. Resistant isolates remained CD4 dependent and were susceptible to enfuvirtide in vitro. Complete coating of CD4(+) T-cell receptors was correlated with serum ibalizumab concentrations. There was no evidence of CD4(+) T-cell depletion in ibalizumab-treated patients. Ibalizumab was not immunogenic, and no serious drug-related adverse effects occurred. In conclusion, ibalizumab administered either weekly or biweekly was safe and well tolerated and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted.

Topics: Adult; Anti-HIV Agents; Antibodies, Monoclonal; Area Under Curve; CD4 Antigens; CD4-Positive T-Lymphocytes; Drug Resistance, Viral; Enfuvirtide; Female; Follow-Up Studies; Half-Life; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Immunity, Cellular; Lymphocytes; Male; Middle Aged; Peptide Fragments; RNA, Viral; Virus Replication; Young Adult

To evaluate the efficacy of adding interleukin-2 (IL-2) to an optimized background treatment in HIV-1 patients with advanced failure.. Randomized, open-label, multicentre controlled trial.. Patients with CD4 T-cell count of less than 200 cells/microl, plasma HIV-1 RNA of more than 10 000 copies/ml and a genotypic sensitivity score showing two or less active drugs were randomized to either eight IL-2 cycles with optimized background treatment or optimized background treatment alone. Optimization was made according to genotypic sensitivity score. Enfuvirtide was added in enfuvirtide-naive patients. Evaluation was performed at week 52 on the proportions of patients with CD4 cell count of at least 200 cells/microl (primary outcome), of patients with a CD4 cell count increase of at least 50 cells/microl from week 0, on plasma HIV-1 RNA and HIV-related events.. Fifty-six patients were analysed. Median age was 43 years, 61% were at Center for Disease Control and Prevention stage C, 43% had a genotypic sensitivity score of 0, median baseline CD4 cell count and plasma HIV-1 RNA values were 64 cells/microl and 4.9 log10 copies/ml, respectively. Treatment could be optimized in 23 patients. At week 52, in the IL-2 and control groups, the proportion of patients with CD4 cell count of at least 200 cells/microl (14 and 18%) or a CD4 cell count increase of at least 50 cells/microl (25 and 32%) and median plasma HIV-1 RNA were not significantly different. In multivariate analysis, optimization with enfuvirtide and baseline CD4 cell count were statistically associated with CD4 cell count of at least 200 cells/microl at week 52 (P = 0.003 and P = 0.01). Optimization with enfuvirtide was the only factor associated with a CD4 cell count gain of at least 50 cells/microl (P < 0.001). There was no difference in the rate of AIDS events between groups.. IL-2 failed to increase CD4 cell count in immunocompromised patients with multiple therapeutic failures. Enfuvirtide use was highly associated with success.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Enfuvirtide; Epidemiologic Methods; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Interleukin-2; Male; Middle Aged; Peptide Fragments; RNA, Viral; Treatment Failure

Among patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection, salvage regimens including enfuvirtide have demonstrated sustained efficacy. Because of reluctance to use subcutaneous injections, raltegravir may be an alternative to replace enfuvirtide within a suppressive regimen. We conducted a prospective, randomized, open-label trial to compare the antiviral efficacy and safety of a switch to raltegravir with the efficacy and safety of continuing enfuvirtide.. A total of 170 patients with multidrug-resistant HIV-1 infection and plasma HIV-1 RNA levels <400 copies/mL who were receiving enfuvirtide-based regimens were randomized 1:1 to maintain enfuvirtide or to switch to raltegravir. The primary efficacy end point was the cumulative proportion of patients with virologic failure, defined as a confirmed plasma HIV-1 RNA level >or=400 copies/mL, over 24 weeks. The secondary end points mainly involved safety.. The switch to raltegravir was non-inferior to the maintenance of enfuvirtide, with virologic failure rates of 1.2% in both treatment arms in the intention-to-treat analysis (beta = 0.01%; 95% confidence interval, -6.7 to 6.8) and 1.2% and 0%, respectively, in the on-treatment analysis (beta = 1.22%; 95% confidence interval, -5.6 to 8.1). At week 24, 88%-89% of patients in both arms had plasma HIV-1 RNA levels <50 copies/mL. No significant CD4 cell count changes occurred in either arm. Grade 3-4 adverse events and laboratory abnormalities were uncommon and were not different between the treatment arms.. A switch to raltegravir was safe, well tolerated, and virologically non-inferior to the maintenance of enfuvirtide in patients infected with multidrug-resistant HIV-1 infection who were receiving suppressive antiretroviral therapy.. NCT00454337

Topics: Adult; Anti-HIV Agents; Drug Resistance, Multiple, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load

The aim of this study was to evaluate the impact of an enfuvirtide-based antiretroviral (ARV) regimen on the management of immunosuppression and follow-up in hepatitis C virus (HCV)/hepatitis B virus (HBV)/human immunodeficiency virus (HIV)-coinfected liver transplant patients in comparison with a lopinavir/ritonavir-based ARV regimen. Tacrolimus and cyclosporine trough concentrations were determined at a steady state during 3 periods: after liver transplantation without ARV treatment (period 1), at the time of ARV reintroduction (period 2), and 2 to 3 months after liver transplantation (period 3). The findings for 22 HIV-coinfected patients were compared (18 with HCV and 4 with HBV); 11 patients were treated with enfuvirtide and were matched with 11 lopinavir/ritonavir-exposed patients. During period 1, tacrolimus and cyclosporine A doses were 8 and 600 mg/day, respectively, and the trough concentrations were within the therapeutic range in both groups. In period 2, the addition of lopinavir/ritonavir to the immunosuppressant regimen enabled a reduction in the dose of immunosuppressants required to maintain trough concentrations within the therapeutic range (to 0.3 mg/day for tacrolimus and 75 mg/day for cyclosporine). Immunosuppressant doses were not modified by the reintroduction of enfuvirtide, there being no change in the mean trough concentrations over the 3 periods. CD4 cell counts remained at about 200 cells/mm3. The HIV RNA viral load remained undetectable. Both groups displayed signs of mild cytolysis and cholestasis due to the recurrence of HCV, whereas no renal insufficiency was observed. Enfuvirtide is an attractive alternative to standard ARV therapy, facilitating the management of drug-drug interactions shortly after liver transplantation. Moreover, the lack of liver toxicity renders this drug valuable in the event of a severe HCV recurrence.

Topics: Adult; Anti-Retroviral Agents; Cyclosporine; Dose-Response Relationship, Drug; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; Humans; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Lopinavir; Male; Middle Aged; Peptide Fragments; Pyrimidinones; Ritonavir; Tacrolimus; Treatment Outcome

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; Humans; Male; Middle Aged; Nitriles; Peptide Fragments; Pilot Projects; Pyridazines; Pyrimidines; RNA, Viral; Treatment Outcome

Enfuvirtide (ENF) administration by needle/syringe is commonly associated with injection site reactions (ISRs). This study assessed ISRs and participant preference between a needle-free injection device (NFID) and a 27-gauge 1/2-inch needle/syringe (NS). A total of 349 participants with human immunodeficiency virus infection, who had difficulty tolerating long-term administration of ENF by NS, underwent randomization (2:1) to ENF administered twice daily by NFID for 8 weeks, or by NS for 4 weeks followed by NFID for 4 weeks. The objectives of the study were to compare ISRs associated with ENF injection using NFID or NS based on a composite endpoint, ISR incidence/severity, overall ISR scores, and discontinuations. In the NFID group, ISRs improved as the percentage of participants meeting the composite endpoint decreased from baseline (40.1%) to week 4 (25.4%) and remained stable at week 8 (21.2%). In the NS --> NFID group, the percentage meeting the composite endpoint worsened from baseline (36.5%) to week 4 (45.1%), but improved at week 8 (26.1%) after switching. Between-participant comparison showed a statistically significant greater improvement from baseline to week 4 in overall ISR score in the NFID group compared to the NS group. Within-participant comparison of the NS --> NFID group showed a significantly greater decrease in overall ISR score from baseline to week 8. In responses to a questionnaire, 87.2% of the participants surveyed preferred the NFID delivery system over NS. NFID is an alternative injection method that may reduce the incidence and severity of treatment-limiting ISRs associated with ENF administration.

Topics: Adult; Enfuvirtide; Equipment Safety; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Injections, Intradermal; Injections, Jet; Male; Middle Aged; Patient Compliance; Patient Satisfaction; Patient Selection; Peptide Fragments; Single-Blind Method; Surveys and Questionnaires

The antiretroviral enfuvirtide (ENF) is injected subcutaneously using a 27-gauge needle. Injection site reactions (ISRs) can affect long-term ENF tolerability. Alternative ENF delivery methods may ameliorate ISRs.. We conducted a multicentre, open-label, randomized controlled trial in which patients receiving ENF were randomized to continue receiving ENF by a 27-gauge needle, a shorter 31-gauge needle or a gas-powered, needle-free injection device (NFID). The primary study endpoint was the proportion of participants with < grade 2 ISR induration at week 12.. Sixty patients received treatment and were included in the intention-to-treat population. The cohort was predominantly male (95%) with a mean age of 49.1 (SD +/- 7.7) years who had injected ENF for a mean of 821 (SD +/- 561) days. Response rates for ISR induration at week 12 were 38%, 25% and 42% for the 27-gauge, 31-gauge and NFID groups, respectively (all pairwise treatment comparison P-values > 0.2). There was no significant between-group difference for any ISR endpoint, except for changes in the composite ISR score (that is, no ongoing pain of > grade 1 or ISR for ongoing pain > or = grade 1 with induration ISR < grade 3 and for nodules < grade 2), which favoured the 27-gauge needle and NFID groups over the 31-gauge group (P = 0.012 and 0.047, respectively). Plasma HIV RNA load was unaffected. There were seven adverse events related to the delivery system: five attributed to the NFID. At week 12, 85% of participants elected to use the NFID.. Needle-free ENF injection offers a reasonable, reliable alternative to needle-based injecting in this population, at least in the short term.

Topics: Adult; Antiviral Agents; Australia; Enfuvirtide; Equipment Design; Female; HIV; HIV Envelope Protein gp41; HIV Infections; Humans; Injections, Jet; Injections, Subcutaneous; Male; Middle Aged; Needles; Pain; Pain Measurement; Patient Satisfaction; Peptide Fragments; RNA, Viral; Skin Diseases; Treatment Outcome; Viral Load

Injection site reactions (ISRs) can present a challenge to patients when using enfuvirtide (ENF). This study compared ISRs associated with use of a needle-free injection device (NFID) with those associated with a standard 27-gauge half-inch needle/syringe (NS).. In this single-blind, crossover study, 58 ENF-naive participants were randomized to self-administer ENF with the NFID for 4 weeks (followed by 4 weeks using NS) or with the NS for 4 weeks (followed by 4 weeks using the NFID). A primary composite endpoint of painful ISR was defined as the combination of grade 1-3 ongoing pain plus either associated grade 3-4 (> or =25 mm) induration or grade 2-4 nodules/cysts (>20 mm). An ISR summary score described ISR frequency/severity. Self-reported device preference was also evaluated at baseline and at study completion.. Fewer participants using NFID experienced the primary composite endpoint of painful ISRs (10/28; 35.7%) compared with NS (20/28; 71.4%) (P=0.004). There was a trend towards a reduced incidence/severity of ISR signs and symptoms with NFID, with significant reductions seen in pain/discomfort and pruritus (P<0.05 and P<0.01, respectively). At the end of the study, most participants (22/25; 88%) expressed a preference for NFID. Haematoma was the sole NFID-related serious adverse event, but this did not lead to discontinuation.. Compared with a standard NS, use of an NFID to administer ENF was associated with a substantially lower incidence of painful ISRs, was generally safe and well-tolerated, and was preferred by most participants in the study.

Topics: Adult; Cross-Over Studies; Enfuvirtide; Equipment Design; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections, Jet; Injections, Subcutaneous; Male; Middle Aged; Needles; Peptide Fragments; Single-Blind Method; Syringes; Treatment Outcome

The aim of the study was to compare the efficacy and safety of induction with the addition of enfuvirtide to a newly designed oral, highly active antiretroviral therapy (HAART) regimen versus HAART alone followed by a maintenance phase wherein participants were randomized to either continue/discontinue enfuvirtide while maintaining HAART or continue HAART alone (NCT00487188).. Participants with HIV-1 RNA >/=1000 copies/mL, CD4 count >/=200 cells/mm(3) and genotype sensitivity score >/=2 (excluding enfuvirtide) were randomized 2:1 to enfuvirtide+HAART or HAART alone and assessed every 4 weeks. Participants achieving <50 copies/mL on two consecutive visits by week 24 entered a maintenance phase wherein those receiving enfuvirtide+HAART underwent another randomization 1:1 to maintain enfuvirtide+HAART or discontinue enfuvirtide; those receiving HAART alone continued their regimen. Virological and immunological endpoints were analysed at weeks 24 and 48.. At 24 weeks, 20/31 (65%) participants in the enfuvirtide+HAART arm versus 8/16 (50%) participants in the HAART arm achieved <50 copies/mL. Median time to achieving <50 copies/mL was 57 versus 141 days in the enfuvirtide+HAART and HAART arms (P = 0.048). Withdrawals were similar between groups. In the maintenance phase, at 48 weeks, 14/19 (74%) in the original enfuvirtide+HAART arm (regardless of second randomization) versus 4/8 (50%) in the HAART arm had <50 copies/mL. During maintenance, there were two virological failures in the enfuvirtide+HAART continuation arm, one in the enfuvirtide discontinuation arm and none in the HAART arm.. Although limited by small participant numbers, these results suggest that treatment with enfuvirtide added to HAART may be an option for many patients.

Topics: Administration, Oral; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; RNA, Viral; Treatment Outcome; Viral Load

Enfuvirtide is the first fusion and entry inhibitor approved for use for the treatment of human immunodeficiency virus (HIV) type 1 infection and as such represents a novel class of agents. For the population of patients experienced with three antiretroviral classes, enfuvirtide provides an additional option for treatment. This prospective, open-label, 24-week, single-arm trial assessed the efficacy and safety of enfuvirtide (90 mg injected subcutaneously twice daily) in combination with darunavir-ritonavir (600/100 mg administered orally twice daily) in triple-antiretroviral-class-experienced adults failing their current regimen. The primary efficacy endpoint was the proportion of participants with plasma HIV RNA loads of <50 copies/ml. Other virological and immunological measures were also evaluated, as were the effects of the baseline viral coreceptor tropism and darunavir phenotype sensitivity scores on the outcomes. At week 24, 60.3%, 72.5%, and 84.0% of 131 participants achieved viral loads of <50 copies/ml and <400 copies/ml and a change from the baseline load of > or =1 log(10) copies/ml, respectively. A baseline viral load of < or =5 log(10) copies/ml was a significant predictor of achieving a viral load of <50 copies/ml at 24 weeks; however, neither background genotype sensitivity nor darunavir phenotype sensitivity was a significant predictor of the achievement of viral loads of <50 copies/ml. Although these findings are limited by the relatively small numbers of participants with darunavir susceptibility changes of > or =10-fold, they suggest that combining enfuvirtide and darunavir-ritonavir with an optimized background regimen in triple-class experienced participants naïve to these agents can result in positive virological and immunological responses regardless of most baseline parameters.

Topics: Adult; Anti-HIV Agents; Darunavir; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Peptide Fragments; Ritonavir; Sulfonamides; Treatment Outcome

The aim of this study was to examine the influence of kidney disease and hemodialysis on the pharmacokinetics ofenfuvirtide.. An open-label, multicenter, parallel group study of HIV-1-infected patients with varying degrees of kidney dysfunction.. A 90-mg dose of enfuvirtide was administered by subcutaneous injection to 3 groups of patients: group A, patients with normal kidney function; group B, patients with chronic kidney disease; and group C, patients with end-stage renal disease (ESRD) requiring dialysis. Patients with ESRD requiring dialysis received the 90-mg dose of enfuvirtide on 2 separate occasions; a dialysis day and a nondialysis day. After each dose, a full 48-hour pharmacokinetic profile was collected and pharmacokinetic parameters were estimated using model-independent techniques.. Enfuvirtide area under the curve (AUCinfinity) and maximum observed enfuvirtide plasma concentration (Cmax) for patients with normal kidney function (group A) was 49.6 microg h/mL and 3.79 microg/mL, respectively. Patients with chronic kidney disease (group B) had higher AUCinfinity (80.3 microg h/mL) and Cmax (5.72 microg/mL), which was similar to patients with ESRD (group C) on both nondialysis days (AUCinfinity 71.1 microg h/mL; Cmax 5.34 microg/mL) and dialysis days (AUCinfinity 66.9 microg h/mL; Cmax 6.31 microg/mL). An average of< 13% of enfuvirtide was removed during the dialysis procedure. The incidence of adverse events was comparable for all study groups.. Enfuvirtide exposure observed in patients with ESRD requiring dialysis or chronic kidney disease was slightly higher than in patients with normal kidney function and similar to historical Cmax and AUC values from studies in patients with normal kidney function. Thus, enfuvirtide does not require dosage adjustment in patients with impaired kidney function.

Topics: Area Under Curve; Dose-Response Relationship, Drug; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Kidney; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Peptide Fragments; Renal Dialysis

High adherence rates to antiretroviral (ARV) therapy are associated with increased durability of viral suppression and decreased rates of drug resistance. The requirement of twice-daily subcutaneous self-administration of enfuvirtide (ENF) has raised concerns about adherence. This study assesses adherence to ENF and an optimized background (OB) of ARVs and its impact on virological and immunological responses during the TORO trials. Eighty-eight percent of patients in the OB arm reported > or = 85% adherence versus 87% of patients in the ENF + OB arm. Higher overall adherence was associated with improved virological and immunological response in both treatment arms at 48 weeks. In patients with > or = 85% adherence, 33% of patients in the ENF + OB arm achieved HIV-1 RNA < 400 copies/ml, versus 13% in the OB arm (p < 0.0001). Similarly, patients with > or = 85% adherence in the ENF + OB arm achieved a mean increase in CD4 cell count of 104 cells/mm(3) compared with 58 cells/mm(3) for patients in the OB arm (p < 0.001). None of the demographic factors explored (age, gender, race) or baseline characteristics (CD4 count, viral load, or baseline sensitivity score) was significant in predicting adherence to ENF when analyzed by multiple regression. Importantly, a history of intravenous drug use (IDU) was not associated with a significant decrease in adherence (mean adherence for IDU 96% versus mean adherence for non-IDU 96%; p = 0.825). Adherence was high in patients receiving the self-injectable ARV enfuvirtide. In addition, the inclusion of ENF did not negatively impact adherence to the ARV regimen as a whole.

Topics: Adult; CD4 Lymphocyte Count; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Middle Aged; Patient Compliance; Peptide Fragments; RNA, Viral; Treatment Outcome; Viral Load

Many antiretroviral drugs continue to exert an anti-human immunodeficiency virus (HIV) benefit in the presence of drug resistance mutations. The degree to which enfuvirtide exerts continued antiviral activity in the presence of incomplete viral suppression has not been defined. To address this question, 25 subjects interrupted enfuvirtide while remaining on a stable background regimen. Enfuvirtide interruption was associated with an immediate but limited increase in plasma HIV-1 RNA levels. Enfuvirtide resistance waned rapidly in the absence of drug pressure and was no longer detectable by week 16 in most individuals. These data indicate that enfuvirtide has measurable antiviral activity in the setting of incomplete viral suppression. Although enfuvirtide resistance mutations are associated with significant fitness defects in vivo, the clinical significance of these mutations remains undefined.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Mutation; Peptide Fragments; RNA, Viral; Treatment Outcome; Withholding Treatment

The objective of this study was to characterize the population pharmacokinetics of enfuvirtide in HIV-1-infected children and adolescents. HIV-infected patients received combination antiretroviral therapy, including enfuvirtide 2.0 mg/kg subcutaneously, twice daily. Serial and trough blood samples were collected up to 48 weeks. NONMEM was used for population pharmacokinetic analysis. Enfuvirtide exposure was calculated from individual parameter estimates derived from the final model. A total of 218 samples from 43 patients were included in the analysis. Enfuvirtide plasma concentration-time data were described by a 1-compartment model with first-order absorption and elimination. The addition of each subject's actual body weight as a covariate affected CL/F but not V/F or K(a). The population CL/F, V/F, and K(a) for a 33-kg reference patient was 1.31 L/h, 2.31 L, and 0.105 h(-1), respectively. The final model was CL/F (L/h) = 1.31 . (body weight/33 [kg])(0.721). Age did not affect enfuvirtide exposure. These results confirm the appropriateness of body weight-based pediatric enfuvirtide dosing.

Topics: Adolescent; Age Factors; Body Weight; Child; Child, Preschool; Creatinine; Demography; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Metabolic Clearance Rate; Peptide Fragments; Racial Groups

In the face of increasing antiretroviral (ARV) treatment options and costs, payers are progressively challenged with prioritising resources. The cost effectiveness of the ARV agent enfuvirtide has been shown to be comparable to that of other available HIV treatment strategies, based on Markov modeling. However, an evaluation of enfuvirtide treatment costs that considers the impact of virological and immunological responses to therapy may provide a more clinically meaningful perspective for primary HIV healthcare providers. The aim of this study was to assess the cost per unit change in efficacy (HIV RNA decreases and CD4 count increases) of three different ARV regimens for triple class-experienced HIV-1 infected patients using actual drug costs and data from randomised, controlled clinical trials.. The analysis included three steps. First, re-analysis of 48-week clinical trial data (T-20 vs Optimized Regimen Only [TORO]) to allow for a more direct comparison of enfuvirtide versus other commonly used ARV agents. All patients included in the re-analysis received a common optimised background (COB) regimen of three drugs: two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and a ritonavir-boosted protease inhibitor (PI), lopinavir. HIV RNA levels and CD4 count changes were determined for three patient groups according to the treatment received - group 1: COB + enfuvirtide; group 2: COB + PI; group 3: COB + NRTI + PI. The second step of the analysis involved calculating the annualised regimen costs ($US wholesaler acquisition cost) for each patient group. In the third step, cost-efficacy ratios were calculated and compared between groups: (a) the annualised regimen cost ($US)/change in viral load from baseline, and (b) the annualised regimen cost ($US)/change in CD4+ cell count from baseline.. One hundred and fifty-seven patients were included in this previously unplanned secondary analysis (group 1: 79 patients; group 2: 42 patients; group 3: 36 patients). HIV RNA and CD4 count changes from baseline to week 48 were -1.80, -0.89 and -0.61 log(10) copies/mL (p < 0.001 for enfuvirtide vs each non-enfuvirtide group) and +102, +57 and +52 cells/mm(3) (p < 0.05 for enfuvirtide versus each non-enfuvirtide subgroup) for groups 1, 2 and 3, respectively. The annualised costs of the combination therapies were $US 35,624, $US 27,549 and $US 30,624; and the costs per 0.50 log(10) copies/mL HIV RNA decrease were $US 9,872, $US 15,542 and $US 24,907 (p < 0.05 for enfuvirtide vs each non-enfuvirtide subgroup) for groups 1, 2 and 3, respectively. The costs per 25 cells/mm(3) CD4 count increase were $US 8,722, $US 12,127 and $US 14,636 for subgroups 1, 2 and 3, respectively. Similar patterns in regimen cost per unit change were achieved after adjusting for baseline prognostic variables. The incremental cost-efficacy ratios for group 1 versus the combination of groups 2 and 3 were $US 3,124 for HIV RNA reduction and $US 3,239 for CD4 count increase.. Enfuvirtide-containing regimens are associated with higher cost as well as improved virological and immunological outcomes when compared with alternative four- and five-drug regimens. When costs and outcomes are considered jointly, an enfuvirtide-based regimen is more cost efficacious than alternative regimens in this patient population.

Topics: Algorithms; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cost-Benefit Analysis; Drug Combinations; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Peptide Fragments; RNA, Viral

TMC125 (etravirine) is a non-nucleoside reverse-transcriptase inhibitor (NNRTI) with activity against NNRTI-resistant HIV-1 in phase IIb trials. The aim of DUET-2 is to examine the efficacy, tolerability, and safety of TMC125 in treatment-experienced patients.. In this continuing randomised, double-blind, placebo-controlled, phase III trial, HIV-1-infected patients on failing antiretroviral therapy with evidence of resistance to currently available NNRTIs and at least three primary protease inhibitor mutations were eligible for enrolment if on stable (8 weeks unchanged) antiretroviral therapy with plasma HIV-1 RNA greater than 5000 copies per mL. Patients were randomly assigned to receive either TMC125 (200 mg) or placebo, each given twice daily with darunavir-ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors, and optional enfuvirtide. The primary endpoint was the proportion of patients with confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00255099.. 591 patients were randomised and treated (295 patients in the TMC125 group and 296 in the placebo group). By week 24, 51 (17%) patients in the TMC125 group and 73 (25%) in the placebo group had discontinued, mainly because of virological failure. 183 (62%) patients in the TMC125 group and 129 (44%) in the placebo group achieved confirmed viral load below 50 copies per mL at week 24 (difference 18%, 95% CI 11-26; p=0.0003). The type and frequency of adverse events were much the same in the two groups.. In treatment-experienced patients, treatment with TMC125 led to better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.

Topics: Adult; Aged; Double-Blind Method; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nitriles; Peptide Fragments; Pyridazines; Pyrimidines; Viral Load

The additional 48-week optional treatment extension of the T-20 versus Optimized Regimen Only (TORO) studies evaluated long-term safety and efficacy of enfuvirtide (ENF) through week 96 in patients receiving ENF plus optimized background (OB) and patients switching to ENF plus OB from OB alone. Patient randomization was 2:1 to ENF plus OB (n = 663) and OB (n = 334), of which 89.7% and 89.8% were male, 89.3% and 88.6% were Caucasian, and median age was 41 and 42 years, respectively. HIV risk factors were comparable between the ENF plus OB and OB groups with the major factors being 65.2% versus 66.2% homosexual contact, 17.8% versus 19.8% heterosexual contact, 4.1% versus 4.8% bisexual contact, respectively, and 6.9% injection drug use in both groups. OB patients were allowed to switch to ENF plus OB at virologic failure before week 48 and required to switch at week 48 to continue in the study (n = 230). Efficacy and safety assessments were conducted for each group. At week 96, 55% of ENF plus OB subjects completed the study and 26.5% achieved a viral load of less than 400 copies per milliliter (17.5% achieved less than 50 copies per milliliter). Viral load and CD4 mean change from baseline was -2.1 and -1.1 log(10) HIV-1-RNA copies per milliliter and +166 and +116 CD4 cells/mm(3) for ENF plus OB and switch patients, respectively. No new ENF-related safety issues emerged in weeks 48-96. Injection site reactions led to discontinuation in 7% and 10% of ENF plus OB and switch patients, respectively. In conclusion, these data demonstrate durable efficacy and safety of ENF over 96 weeks and that early use of ENF in combination with other agents for the treatment of antiretroviral-experienced HIV-infected subjects is beneficial.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Peptide Fragments; RNA, Viral; Time Factors; Treatment Outcome; Viral Load

Analysis of CD4 cell responses during 48 weeks of enfuvirtide therapy after virological failure (analysis of covariance) demonstrated significant associations between V38 mutations (n = 58 subjects) and continued CD4 cell increases and between Q40 mutations (n = 8) and loss of CD4 cell benefit (+34 versus -95 cells/mul, P < 0.001). Subjects with N43 (n = 20) or other mutations (n = 48) had intermediate CD4 cell responses. These data suggest that key enfuvirtide resistance mutations may be associated with reduced viral pathogenicity in vivo.

Topics: CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Mutation; Peptide Fragments; Retrospective Studies

The aim of this study was to investigate the susceptibility to T20 and the dynamics of amino acid changes in HR1 and HR2 of gp41 of HIV-1 obtained from plasma, peripheral blood mononuclear cells (PBMC), and primary isolates (PI) in four highly antiretroviral-experienced patients. These patients received T20 plus an antiretroviral regimen and were followed-up over a period of 40-72 weeks. In one non-responder patient, N43D substitution was detected at 12 weeks of treatment, in association with a value of T20-IC50 of 10 microg/ml (10-fold increase). Double mutations N42T + N43D were observed in plasma RNA at 32 weeks and remained detectable up to 16 weeks after the withdrawal of the drug. The S138A substitution in HR2 was observed in plasma RNA at 32 weeks, and both in plasma RNA and in PI DNA at 40 weeks, associated with an increase of the T20-IC50 to 25 microg/ml (25-fold increase). Mutations V101G and E137K, not reported previously, were also observed in the HR2 region. Whether these new substitutions play a role in T20 resistance needs to be examined. In three temporary responders, coinciding with viral load rebound, G36D, and N42T substitutions were observed at 12, 24, and 40 weeks. G36D mutation was associated with a value of T20-IC50 of 5 microg/ml. The HR2 S138A mutation was detected after the detection of HR1 substitutions and was associated with an increase in the level of T20-IC50 to 125 microg/ml (125-fold increase) All these data reinforce the role of gp41 amino acids 36-45 and the potential influence of the HR2 S138A mutation in the genotypic/phenotypic resistance to T20.

Topics: Amino Acid Sequence; Amino Acid Substitution; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; DNA, Viral; Dose-Response Relationship, Drug; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation; Peptide Fragments; Proviruses; RNA, Viral; Salvage Therapy; Sequence Alignment; Treatment Outcome

To investigate the pharmacokinetics, safety/tolerability and antiviral activity of enfuvirtide administered once-daily (QD) versus twice-daily (BID).. An open-label, randomized, multiple dose, two-period crossover study comparing 180 mg enfuvirtide, two injections QD versus 90 mg enfuvirtide, two injections, BID.. Steady-state intensive pharmacokinetic samples were obtained on days 7 and 14.. Thirty-seven subjects received at least one dose of enfuvirtide. Thirty-three subjects completed both dosing periods. The regimens were bioequivalent based on the ratio of geometric mean area under the curve (AUC)0-tau [112 +/- 6.2 microg x h/ml QD; 115 +/- 6.4 microg x h/ml 2 x BID; QD/BID 0.98; 90% confidence interval (CI) 0.89,1.07]. The maximum observed plasma concentration within a dosing interval (Cmax) was 49% higher for QD (9.5 +/- 2.7 microg/ml) versus BID (6.3 +/- 1.7 microg/ml) and the pre-dose plasma concentration (Ctrough) was 57% lower for QD (1.6 +/- 1.1 microg/ml) versus BID (3.8 +/- 1.3 microg/ml). The LSM decrease in viral load from baseline to day 7 was 1.0 +/- 0.14 log10 (n = 18) for QD and 1.4 +/- 0.2 log10 (n = 17) for BID (LSM difference 0.385; P = 0.07). Linear regression analysis suggested that decline in viral load up to day 7 was associated with Ctrough but not Cmax or AUC. There were no significant differences in adverse events between the two dosing regimens.. Administration of enfuvirtide 180 mg QD results in bioequivalence compared with 90 mg BID based on AUC with a similar short-term safety profile, but a trend towards a weaker antiretroviral effect. Larger and longer-term studies are needed to determine if 180 mg once daily is an effective dosing alternative for enfuvirtide.

Topics: Adult; Area Under Curve; Cross-Over Studies; Dose-Response Relationship, Drug; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Peptide Fragments

To assess the use of the Biojector B2000 needle-free gas-powered injection system for subcutaneous administration of enfuvirtide in HIV-infected patients and to compare this system with standard needles and syringes with respect to ease of use, severity of injection site reactions (ISR), and enfuvirtide plasma levels.. An observational study among 32 treatment-experienced HIV clinic patients receiving enfuvirtide.. Adult patients were assessed before and after switching from standard needles to the Biojector for enfuvirtide administration. Patients used the Biojector for up to 24 weeks and rated ease of use from 0 (easy) to 3 (difficult). ISR were graded from 0 to 31 for signs and symptoms (erythema, induration, pruritus, nodules/cysts, ecchymosis), duration of individual lesions, and number of lesions. Plasma was collected pre-dose and 1 h post-dose for enfuvirtide measurement. The high-pressure liquid chromatography with tandem mass spectrometry method used was specific for enfuvirtide over its known plasma metabolite. Wilcoxon rank sum tests were used to compare needle-based and Biojector outcomes.. The Biojector was rated as being significantly easier to use (P < 0.001) and reduced the occurrence of ISR compared with standard needles (P < 0.001). Enfuvirtide plasma levels were not statistically different between the two administration methods at either pre-dose trough (P = 0.41) or 1 h post-dose (P = 0.74).. The Biojector needle-free injection system was easy to use for enfuvirtide administration and was associated with a decreased severity of ISR. Plasma enfuvirtide levels pre-dose and 1 h post-dose were comparable when injecting with standard needles or the Biojector.

Topics: Adult; Enfuvirtide; Equipment Design; Follow-Up Studies; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Injections, Jet; Needles; Patient Satisfaction; Peptide Fragments; Skin; Statistics, Nonparametric; Syringes

To assess if enfuvirtide (ENF) increases antiviral activity of a highly active four-drug antiretroviral (ARV) regimen containing lopinavir/ritonavir, efavirenz, lamivudine and tenofovir in ARV-naive, HIV-infected patients.. Pilot study in ARV-naive, HIV-infected patients with viral load (VL) >10,000 copies/ml and no documented resistance to any of the study drugs. Patients were randomized to receive ENF (ENF Group) or not (Control Group) in combination with lopinavir/ritonavir, efavirenz, lamivudine and tenofovir as a backbone. The primary endpoint was to assess differences in the HIV-1 RNA decay rate during the first phase of viral decay. VL and treatment adherence were measured at baseline, every 6 h during the first 3 days, and once daily from day 3 to 6. Individual HIV-1 RNA decay rates were obtained using a non-linear least squares regression model.. Eight subjects were included in each study group. Mean (SD) baseline VL was 4.98 (0.38) log10 copies/ml in the ENF Group and 5.10 (0.49) log10 copies/ml in the Control Group (P=0.607). Baseline CD4+ cell count was 463 (306) and 362 (225) cells/mm3 in the ENF and the Control Group, respectively (P=0.484). First phase HIV-1 RNA decay rate was 0.802 (0.127) d(-1) in the ENF Group and 0.624 (0.182) d(-1) in the Control Group (P=0.045). By day 6, VL was 3.55 (0.40) and 3.92 (0.36) log10 copies/ml in the ENF and the Control Group, respectively (P=0.079).. The addition of ENF increased the antiviral potency of a highly active four-drug ARV regimen by 28.5% in ARV-naive, HIV-infected patients. The clinical impact of this finding should be assessed.

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Synergism; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Lamivudine; Lopinavir; Organophosphonates; Oxazines; Patient Compliance; Peptide Fragments; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Tenofovir; Treatment Outcome

Most individuals with multidrug-resistant HIV who switch to a new therapeutic regimen containing a single fully effective agent experience incomplete viral suppression. We postulated that interruption of antiretroviral therapy prior to the introduction of such a regimen would improve long-term virological outcomes. Thirty, three-class experienced, enfuvirtide-naive individuals with detectable drug-resistant viraemia were randomized to an immediate enfuvirtide/optimized-background treatment regimen or a 16-week treatment interruption followed by enfuvirtide/optimized-background treatment regimen. The median CD4+ T-cell count and viral load at study entry were 39 cells/mm and 4.72 log10 copies RNA/ml, respectively. There was no evidence of any virological or immunological benefit associated with the interruption. In multivariate analysis, only the baseline phenotypic susceptibility score was predictive of treatment response at week 48 (P=0.009). Only 40% of individuals had evidence of a shift in drug-resistance genotype during the interruption. In summary, interrupting therapy prior to initiating salvage therapy in patients with advanced disease did not result in an improved virological response to enfuvirtide. The collective predictive activity of an enfuvirtide-containing regimen was important in predicting treatment response.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Microbial Sensitivity Tests; Peptide Fragments; Pilot Projects; RNA, Viral; Treatment Outcome

We wished to assess, in heavily treatment-experienced patients, the prevalence of and baseline characteristics associated with HIV-1 coreceptor use and their relationship to responses to enfuvirtide treatment.. Samples were obtained from participants in phase 3 studies of enfuvirtide. Multiple logistic regression and analysis of covariance were performed on data for baseline coreceptor use, virological and immunological response, and changes in coreceptor use during treatment.. Baseline envelopes were phenotyped for 724 patients; 50% harbored R5 strains, 48% harbored dual/mixed (D/M) strains, and 2% harbored X4 strains. D/M strains were associated with significantly lower CD4(+) cell counts but comparable viral loads, compared with R5 strains (P=.0005). Virological and immunological responses to enfuvirtide-based treatment showed no correlation with baseline coreceptor use. Changes in virus tropism from D/M to R5 strains during treatment were common, particularly in patients who received enfuvirtide (27%, vs. 14% who received no enfuvirtide; P<.05).. At baseline, D/M strains were associated with lower CD4(+) cell counts but similar viral loads, compared with R5 strains, and were common across CD4(+) cell count strata. The comparable virological and immunological responses and bias toward shifts from D/M to R5 strains in patients who received enfuvirtide support its use in triple-class treatment-experienced patients and its study as a therapeutic partner for coreceptor-binding inhibitors.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; Humans; Male; Middle Aged; Peptide Fragments; Prevalence; Receptors, HIV; RNA, Viral; Time Factors; Treatment Outcome; Viral Load

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.

Topics: Adult; Aged; Anti-HIV Agents; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viral Load

The aim of this pilot study was to assess whether enfuvirtide can be discontinued in patients on long-term viral suppression. Eight patients with multidrug-resistant virus were randomly assigned to stop and 10 subjects to continue enfuvirtide. At week 48, viral rebound occurred in five (62.5%) and in no patients, respectively, (P = 0.007). The CD4 cell decrease in failure patients was 5% (P = ns). These results suggest that enfuvirtide should be maintained until new active drugs became available.

Topics: ADP-ribosyl Cyclase 1; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Drug Resistance, Viral; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Mutation; Peptide Fragments; Pilot Projects; Prospective Studies

Amdoxovir (2,6-diaminopurine dioxolane; DAPD) is a nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus-1 (HIV-1) with activity against wild-type and NRTI-resistant viruses.. ACTG A5118 assessed the antiretroviral activity and safety of DAPD (300 mg orally, twice daily) versus placebo in combination with enfuvirtide (ENF) plus an optimized background (OB) regimen in subjects with failure of two or more antiretroviral (ARV) regimens. The primary endpoints for comparison were time-averaged area under the curve minus baseline (AAUCMB) of plasma HIV-1 RNA concentration at 24 weeks and time to first serious (DAIDS toxicity table Grade > or = 3) adverse event (AE). An unplanned interim review recommended closing enrollment because the study was unlikely to demonstrate a difference between arms. The 18 subjects on study, nine in each arm, were unblinded and allowed to continue study treatment through 48 weeks.. Intention-to-treat analysis showed the median AAUCMB was -0.9 log10 copies/mL (95% CI = -2.2, -.0.1) in the DAPD arm and -0.9 log10 copies/ml (95% CI = -1.1, -0.1) in the placebo arm (P = 0.69). Median CD4+ T-cell increase was 79 cells/mm3 (95% CI =1, 115) in the DAPD arm and 60 (95% CI =1, 101) in the placebo arm (P = 0.45). Time to first serious AE did not differ between arms (P = 0.91). Mild decreases of creatinine clearance were observed with similar frequency between arms; no subject developed lens opacities.. Addition of DAPD to ENF plus OB in advanced subjects with highly resistant virus appeared safe, but did not add statistically significant antiretroviral activity at 24 weeks in this small study.

Topics: Adult; CD4 Lymphocyte Count; Dioxolanes; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Pilot Projects; Purine Nucleosides; Reverse Transcriptase Inhibitors; Treatment Failure; Viral Load

The availability of enfuvirtide enables assessment of whether human immunodeficiency virus (HIV) decay can be enhanced by targeting reverse transcriptase, protease, and fusion. We performed a 12-week study of 22 patients randomized to receive ritonavir-boosted saquinavir and efavirenz with (the 3-target arm) or without (the 2-target arm) enfuvirtide. We observed no difference in the mean+/-SD elimination-rate constant for overall decay (0.142+/-0.040 per day and 0.128 +/- 0.033 per day in the 2- and 3-target arms, respectively; P>.1) or for modeled first-phase decay rate (-0.62+/-0.34 per day and -0.51+/-0.16 per day; P>.1). Antiretroviral therapy that inhibits HIV reverse transcriptase and protease exerts potent antiviral effects that might not be augmented by the addition of an HIV fusion inhibitor.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Oxazines; Peptide Fragments; Ritonavir; Saquinavir; Viral Load

To compare the relative bioavailability of enfuvirtide, a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, injected with the Biojector 2000 (B2000) needle-free device versus a 27-gauge half-inch needle-syringe; and to assess safety, tolerability, and patient preference for the two devices.. Open-label, randomized, two-period crossover bioequivalence evaluation.. Clinical research center.. Twenty-seven adults with HIV-1 viral loads below 1000 copies/ml.. Each patient received enfuvirtide 90 mg subcutaneously with the B2000 and with the needle-syringe, with a 1-week washout between treatments.. Twenty-six and 27 patients were included in the bioequivalence and safety analyses, respectively. Plasma enfuvirtide concentrations were measured at baseline and at several intervals after each injection. The B2000:needle-syringe ratios of maximum concentration (C(max)), area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-infinity)), and AUC from time zero to tau (dosing interval) (AUC(0-tau)) served as criteria for bioequivalence determination. The two drug delivery systems were considered bioequivalent if the 90% confidence intervals (CIs) for the ratios were within 0.8-1.25. Safety and tolerability were evaluated based on documentation of adverse events, graded laboratory toxicities, and local injection-site reactions. Patient surveys provided feedback on device preference. Ratios of C(max), AUC(0-infinity), and AUC(0-tau) were 0.95 (90% CI 0.84-1.09), 0.99 (90% CI 0.93-1.05), and 0.99 (90% CI 0.93-1.05), respectively. The frequency of injection-site reactions was low, and severity was generally mild for both devices. Survey results showed 18 patients (69%) had a positive overall impression of the B2000 and 14 (54%) felt safer injecting with this device. Overall, 17 patients (65%) preferred the B2000 over the needle-syringe.. Bioavailability of enfuvirtide with the B2000 and needle-syringe was equivalent based on C(max), AUC(0-tau), and AUC(0-infinity). Safety profiles and injection-site reactions were comparable between the devices, but patients preferred the B2000. Delivery of enfuvirtide with the B2000 is a feasible alternative to standard needle administration and warrants further evaluation.

Topics: Area Under Curve; Cross-Over Studies; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections, Jet; Injections, Subcutaneous; Male; Middle Aged; Patient Satisfaction; Peptide Fragments; Therapeutic Equivalency

Antiretroviral regimens containing the fusion inhibitor enfuvirtide (ENF) are associated with sustained viral suppression and immunological benefit. However, local injection site reactions (ISR) occur in the majority of patients. The aim of this study was to determine the pathogenesis of ISRs.. Injection sites were evaluated prospectively from 30 min up to 15-30 days post-injection in ENF-experienced (Cohort I) and ENF-naive patients (Cohort II) during the first 2 weeks of therapy. Four to five injections were given in rotating abdominal sites by a nurse using a standardized technique and were rigorously evaluated.. Reactions were observed in 80-100% of patients; the majority of the reactions were mild to moderate, generally appeared within 24-48 h post-injection, and pain, induration and erythema were the most common clinical signs. Whereas most patients experienced ISRs, the overall prevalence in Cohort II was low (35% maximum). Punch biopsies of injection sites in Cohort I consisted primarily of mixed lymphocytic infiltrates with eosinophils and neutrophils. Injection vehicle (ENF buffer minus ENF) and reduced volume (2 x 0.5 ml ENF [45 mg] versus 1.0 ml [90 mg] ENF) were investigated in Cohort II. Fewer reactions appeared with vehicle and pain was absent with the smaller injection volume. Pathology was indistinguishable between ENF, vehicle and normal tissue in Cohort II patients.. These results suggest that injection technique, injection volume and peptide may influence ISR to ENF.

Topics: Abdomen; Adult; Biopsy; Cohort Studies; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Injections, Intraperitoneal; Leukocytes; Male; Middle Aged; Pain; Peptide Fragments; Prospective Studies; Time Factors

T-1249 is a 39-amino acid synthetic peptide fusion inhibitor (FI) shown to preserve antiretroviral activity in vitro against human immunodeficiency virus (HIV) isolates that have decreased susceptibility to enfuvirtide (ENF).. A 10-day phase 1/2 study of the safety and antiretroviral activity of T-1249 was conducted in 53 HIV-1-infected adults with detectable viremia while on an ENF-containing treatment regimen.. From FI-naive baseline levels, the geometric mean (GM) decrease in susceptibility to ENF was 116.3-fold, and the GM decrease in susceptibility to T-1249 was 2.0-fold. Patients continued to administer their failing treatment regimen but replaced ENF with T-1249 at a dose of 192 mg/day. T-1249 was generally well tolerated; injection site reactions, which were generally mild, were the most commonly reported adverse event (64% of patients). The median change from levels of HIV-1 RNA at baseline to levels on day 11 was -1.26 log(10) copies/mL (95% confidence interval, -1.40 to -1.09 log(10) copies/mL); on day 11, a decrease from baseline HIV-1 RNA levels of >/=1.0 log(10) copies/mL was seen in 73% of patients. Antiretroviral activity, as measured by levels of HIV-1 RNA, was not predicted by baseline susceptibility to T-1249 or to ENF; genotypic substitutions that emerged during T-1249 treatment were identified in virus from some patients.. These results indicate that FIs constitute an expanding class of antiretroviral agents with the potential to be sequenced.

Topics: Adult; Drug Resistance, Viral; Enfuvirtide; Female; Genotype; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Peptide Fragments; Phenotype; Pregnancy; RNA, Viral; Treatment Failure

Enfuvirtide (ENF) has been shown to improve short-term virologic responses when given to highly treatment-experienced patients with advanced HIV disease. Because of the high cost of ENF compared with other antiretroviral agents, our objectives were to determine the potential long-term clinical impact and cost-effectiveness of ENF in these patients.. We used a computer simulation model of HIV disease to project life expectancy, quality-adjusted life expectancy, cost, and cost-effectiveness of ENF in treatment-experienced patients. Input data were from the T-20 versus Optimized Regimen Only (TORO) 1 and 2 trials, 2 studies comparing ENF plus an optimized background regimen (OBR) with an OBR alone.. ENF plus an OBR increased projected discounted quality-adjusted life expectancy from 45.4 months with an OBR alone to 54.9 months, a difference of 9.5 quality-adjusted life-months. At the current annual ENF cost of US 18,500 dollars per year (in 2001 US dollars), the incremental cost-effectiveness ratio for ENF plus an OBR was US 69,500 dollars per quality-adjusted life-year (QALY) compared with an OBR alone. When 48-week virologic suppression rates for ENF plus an OBR were varied from a 50% reduction to a 250% increase in the suppression rate attributable to ENF, gains in quality-adjusted life expectancy ranged from 4.5 to 25.9 quality-adjusted life-months compared with an OBR alone, with cost-effectiveness ratios ranging from US 97,900 dollars per QALY to US 52,300 dollars per QALY gained. If ENF is continued after the HIV RNA level returns to the pretreatment baseline, the cost-effectiveness ratio increases to US 168,200 dollars per QALY.. In highly treatment-experienced patients, ENF plus an OBR provides substantial gains in quality-adjusted life expectancy compared with an OBR alone. Although ENF plus an OBR is less cost-effective than other commonly used interventions in HIV disease, its use may be justified, given the poor prognosis of these patients and their otherwise limited options for antiretroviral therapy.

Topics: Adult; CD4 Lymphocyte Count; Cost-Benefit Analysis; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Middle Aged; Peptide Fragments; Quality of Life; Reproducibility of Results; Sensitivity and Specificity; Survival Analysis; United States

The effect of therapy with a combination of tenofovir and full-dose didanosine on increases in CD4+ cell count was examined in 2 large trials of treatment-experienced patients with human immunodeficiency virus (HIV) infection (the T-20 versus Optimized Regimen Only [TORO] 1 and 2 clinical trials). Individuals receiving both agents showed little additional increase in CD4+ cell count after week 8 of therapy, whereas those receiving 1 or neither of the agents had continuous increases over a 48-week period.

Topics: Adenine; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Organophosphonates; Peptide Fragments; Tenofovir; Time Factors; Viral Load

The T-20 Versus Optimized Background Regimen Only (TORO) 1 and TORO 2 clinical trials are open-label, controlled, parallel-group, phase 3 studies comparing enfuvirtide plus an optimized background (OB) of antiretrovirals (n = 661) with OB alone (n = 334) in treatment-experienced HIV-1-infected patients.. The primary objective at week 48 was to investigate durability of efficacy, as measured by the percentage of patients maintaining their week 24 response or improving. Efficacy analyses used the intent-to-treat population.. A total of 73.7% of patients randomized to the enfuvirtide group remained on treatment through week 48 versus 21.3% originally randomized to the control group. At week 48, a higher proportion of week 24 responders maintained their response or were new responders in the enfuvirtide group than in the control group in each responder category: HIV-1 RNA level > or =1.0 log(10) change from baseline, <400 copies/mL and <50 copies/mL (37.4%, 30.4%, and 18.3% in the enfuvirtide group vs. 17.1%, 12.0%, and 7.8% in the control group, respectively; P < 0.0001 for all comparisons). CD4 cell count increases from baseline were twice as great in the enfuvirtide group as in the control group.. These data demonstrate durable efficacy of enfuvirtide plus OB over 48 weeks.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; RNA, Viral; Time Factors; Viral Load

Antiretroviral tolerability is a critical factor contributing to treatment outcome. The T-20 Versus Optimized Background Regimen Only (TORO) studies assessed the safety and efficacy of enfuvirtide in treatment-experienced HIV-1-infected patients.. A total of 997 patients were randomized at a 2:1 ratio to an optimized background antiretroviral regimen plus enfuvirtide (n = 663) or an optimized background regimen alone (control group; n = 334). Control patients could switch to enfuvirtide on virologic failure.. In total, 26.5% of patients randomized to enfuvirtide and 36.6% to the control group discontinued study treatment before week 48; the percentage of patients withdrawn for safety reasons (including adverse events [AEs], deaths, and laboratory abnormalities) was 14.0% in the enfuvirtide group and 11.6% in the control group. Injection site reactions (ISRs) occurred in 98% of enfuvirtide patients and led to treatment discontinuation in 4.4%. Treatment-related (defined as possibly, probably, or remotely) AE rates per 100 patient-years were lower with enfuvirtide (96.2) than in the control group (149.9); diarrhea, nausea, and fatigue, the most frequently reported AEs, were significantly less frequent with enfuvirtide than in the control group. Pneumonia was significantly more frequent in patients treated with enfuvirtide (6.7 vs. 0.6 events per 100 patient-years), although the incidence was within expected ranges for this population. Lymphadenopathy was also higher in enfuvirtide-treated patients (7.1 vs. 1.2 events per 100 patient-years) for control patients.. The addition of enfuvirtide to an optimized background regimen does not exacerbate AEs commonly associated with antiretrovirals. ISRs limited treatment in <5% of patients.

Topics: Adult; Anti-HIV Agents; Diarrhea; Drug Therapy, Combination; Enfuvirtide; Fatigue; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Lymphatic Diseases; Nausea; Peptide Fragments; Pneumonia

Enfuvirtide is the first fusion inhibitor to be approved by the Food and Drug Administration for the treatment of chronic human immunodeficiency virus (HIV) infection in adults and children 6 years and older. The drug is a synthetic peptide derived from a naturally occurring amino acid sequence known as heptad repeat 2 (HR2) found in gp41, a viral transmembrane glycoprotein that facilitates fusion with host cells. By mimicking the activity of HR2 and competitively binding to a second region of gp41, heptad repeat 1 (HR1), enfuvirtide prevents interaction between HR1 and HR2 and inhibits the conformational change of gp41 that is necessary for fusion of virions to host cells. The safety and efficacy of enfuvirtide have been studied only in antiretroviral-experienced persons. Preliminary data from two multicenter phase III clinical trials (T-20 versus Optimized Regimen Only [TORO 1, TORO 2]) suggest that the drug is safe and efficacious in heavily pretreated subjects through 24 weeks. By week 24, in TORO 1 and TORO 2, respectively, mean changes in HIV RNA concentrations of -1.7 and -1.4 log10 copies/ml were observed in subjects receiving enfuvirtide plus an optimized background (OB) regimen, compared with changes of -0.8 and -0.7 log10 copies/ml in subjects receiving an OB regimen alone. Resistance to enfuvirtide has been identified in vitro and in vivo. Most resistant variants contain mutations in the HR1 region of gp41 (positions 36-45). In phase III clinical trials, numerous substitutions within this critical region were associated with faster time to virologic failure over 24 weeks. Overall, enfuvirtide appears to be well tolerated and acceptable to patients despite a high rate of injection site reactions (> 90%). Bacterial pneumonia and eosinophilia occurred more frequently in subjects taking enfuvirtide than in those taking an OB regimen alone in phase III trials; however, no causal relationship was established. Like most drugs with peptide structures, enfuvirtide appears to have a low potential for metabolic drug-drug interactions. The approved dosage is 90 mg twice/day by subcutaneous injection in adults and 2 mg/kg twice/day in children older than 6 years. Enfuvirtide is an addition to antiretroviral therapy since it targets a new step in the HIV life cycle. Given the complexity of its production and administration, however, it is likely to be most useful in antiretroviral-experienced patients.

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections, Subcutaneous; Peptide Fragments

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 drug to block human immunodeficiency virus type 1 (HIV-1) glycoprotein 41-mediated viral fusion to host cells. This study investigated whether enfuvirtide can influence the activities of cytochrome P450 (CYP) enzymes in HIV-1-infected patients.. An open-label, 1-sequence crossover study was conducted in 12 HIV-1-infected adults, by use of a 5-drug cocktail consisting of caffeine, chlorzoxazone, dapsone, debrisoquin (INN, debrisoquine), and mephenytoin to assess the activities of CYP1A2, CYP2E1, CYP3A4, CYP2D6, and CYP2C19, respectively. Dapsone was used to assess N-acetyltransferase activity. Patients received a single dose of the cocktail alone on day -15 and another together with enfuvirtide on day 6. Enfuvirtide (90 mg subcutaneously) was administered twice daily on days 1 to 7. Phenotypic index parameters were estimated and analyzed by ANOVA with factors subject and day (-15 and 6).. The phenotypic index parameters, with and without enfuvirtide, for CYP3A4 (0.33 versus 0.34; 90% confidence interval [CI] for ratio of least squares means, 0.88-1.09), CYP2D6 (0.72 versus 0.71; 90% CI, 0.97-1.06), and N-acetyltransferase (0.35 versus 0.39; 90% CI, 0.82-0.98) were bioequivalent. The phenotypic index parameters, with and without enfuvirtide, for CYP1A2 (0.76 versus 0.81; 90% CI, 0.71-1.17), CYP2E1 (1.3 versus 1.2; 90% CI, 0.87-1.29), and CYP2C19 (93 versus 81.8; 90% CI, 0.98-1.28) were not bioequivalent but were not substantially different.. Enfuvirtide had no clinically important effect on the metabolism of probe drugs mediated by CYP3A4, CYP2D6, or N-acetyltransferase and had little effect on the metabolism of drugs mediated by CYP1A2, CYP2E1, or CYP2C19. The potential for interactions between enfuvirtide and concomitantly administered drugs metabolized by the CYP enzymes tested in this study is low.

Topics: Adult; Aged; Analysis of Variance; Confidence Intervals; Cross-Over Studies; Cytochrome P-450 Enzyme System; Drug Interactions; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Phenotype

Enfuvirtide (Fuzeon) is an HIV fusion inhibitor, the first drug in a new class of antiretrovirals. The HIV protease inhibitors ritonavir and saquinavir both inhibit cytochrome P450 (CYP450) isoenzymes, and low-dose ritonavir is often used to boost pharmacokinetic exposure to full-dose protease inhibitors. These two studies were designed to assess whether ritonavir and ritonavir-boosted saquinavir influence the steady-state pharmacokinetics of enfuvirtide. Both studies were single-center, open-label, one-sequence crossover clinical pharmacology studies in 12 HIV-1-infected patients each. Patients received enfuvirtide (90 mg twice daily [bid], subcutaneous injection) for 7 days and either ritonavir (200 mg bid, ritonavir study, orally) or saquinavir/ritonavir (1000/100 mg bid, saquinavir/ritonavir study, orally) for 4 days on days 4 to 7. Serial blood samples were collected up to 24 hours after the morning dose of enfuvirtide on days 3 and 7. Plasma concentrations for enfuvirtide, enfuvirtide metabolite, saquinavir, and ritonavir were measured using validated liquid chromatography tandem mass spectrometry methods. Efficacy and safety were also monitored. Bioequivalence criteria require the 90% confidence interval (CI) for the least squares means (LSM) of C(max) and AUC(12h) to be between 80% and 125%. In the present studies, analysis of variance showed that when coadministered with ritonavir, the ratio of LSM for enfuvirtide was 124% for C(max) (90% confidence interval [CI]: 109%-141%), 122% for AUC(12h) (90% CI: 108%-137%), and 114% for C(trough) (90% CI: 102%-128%). Although the bioequivalence criteria were not met, the increase in enfuvirtide exposure was small (< 25%) and not clinically relevant. When administered with ritonavir-boosted saquinavir, the ratio of LSM for enfuvirtide was 107% for C(max) (90% CI: 94.3%-121%) and 114% for AUC(12h) (90% CI: 105%-124%), which therefore met bioequivalence criteria, and 126% for C(trough) (90% CI: 117%-135%). The pharmacokinetics of enfuvirtide are affected to a small extent when coadministered with ritonavir at a dose of 200 mg bid but not when coadministered with a saquinavir-ritonavir combination (1000/100 mg bid). However, previous clinical studies have shown that such increases in enfuvirtide exposure are not clinically relevant. Thus, no dosage adjustments are warranted when enfuvirtide is coadministered with low-dose ritonavir or saquinavir boosted with a low dose of ritonavir.

Topics: Adult; Area Under Curve; Cross-Over Studies; Drug Interactions; Drug Therapy, Combination; Enfuvirtide; Female; Half-Life; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Peptide Fragments; Ritonavir; Saquinavir

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.

Topics: Amino Acid Sequence; Amino Acid Substitution; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Resistance, Viral; Enfuvirtide; Gene Products, pol; Genes, env; Genes, pol; Genes, Viral; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Lymphocyte Activation; Macrophages; Molecular Sequence Data; Mutation, Missense; Peptide Fragments; Receptors, CCR5; Receptors, CXCR4; RNA, Viral; Salvage Therapy; T-Lymphocytes, Cytotoxic; Viremia

Enfuvirtide, a peptide inhibitor of human immunodeficiency virus (HIV)-1-host cell membrane fusion, is the first of a new class of antiretroviral agents, the entry inhibitors. The safety and antiretroviral activity of enfuvirtide treatment of 24 weeks in HIV-1-infected children has been previously documented. Here we present the long term tolerability and safety of enfuvirtide.. Fourteen children, 4 to 12 years of age, with incompletely suppressed HIV-1 infection were evaluated. Enfuvirtide was administered twice daily by subcutaneous injection. After the first 24 weeks of enfuvirtide dosing, subjects were evaluated every 8 weeks up to 96 weeks of therapy. At each visit, each subject had a physical examination and an assessment for adverse events with particular attention to evaluation of injection site reactions. Laboratory studies obtained at each visit included hematology and blood chemistry values, plasma HIV-1 RNA concentrations and CD4+ T cell counts.. Of 14 subjects, 6 completed at least 96 weeks of treatment. One child discontinued enfuvirtide after 22 days of treatment because of an aversion to injections, and 1 child electively discontinued after week 24 because of surgical complications unrelated to study drug. Four subjects discontinued study because of virologic failure, defined as an increase or persistence of plasma HIV-1 RNA 1.0 copies/mL above baseline, which occurred between >or =log10 weeks 40 and 63. Two children experienced grade 3 adverse events resulting in discontinuation of the study drug; 1 subject developed grade 3 thrombocytopenia and 1 developed grade 3 edema at weeks 65 and 77, respectively. Eleven of 14 children had local injection site reactions during the first 24 weeks of treatment, 4 of the 12 subjects who continued treatment beyond week 24 reported local reactions. Generally, these local reactions were 1- to 3-cm tender nodules that developed after the injections and lasted for 1-2 days. Twelve children developed new diagnoses during treatment with enfuvirtide. None was judged to be definitively related to the study drug. Thirty-six percent of children starting enfuvirtide had HIV-1 RNA levels > 1 log10 copies/mL below baseline levels at week 96. Children remaining on enfuvirtide for the entire 96 weeks had a median of 65 cells/mm and 9% increase in CD4+ T cells.. Enfuvirtide was generally safe and, except for a high rate of injection site reactions, well-tolerated in HIV-1-infected children for as long as 96 weeks.

Topics: Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Injections, Subcutaneous; Male; Peptide Fragments; RNA, Viral

Enfuvirtide (ENF) is the first of a novel class of drugs that block HIV gp41-mediated viral fusion to host cells. Viruses with mutations at positions 36-38 in HIV-1 gp41 and/or reduced susceptibility to ENF have been selected both in vitro and in vivo.. An analysis of baseline and on-treatment ENF susceptibility in virus samples from Phase II clinical trial patients treated with ENF as functional monotherapy for 28 days (TRI-003) or in combination with oral antiretrovirals for >/= 48 weeks (T20-205, T20-206 and T20-208). Population sequencing identified amino acid (aa) substitutions at positions 36-45 of gp41 in plasma HIV-1. ENF susceptibility of virus isolates was tested in the cMAGI assay and viral DNA was sequenced for selected isolates.. HIV-1 gp41 aa 36-45 were highly conserved in virus from ENF-naive patients, except for a 15% incidence of N42S which did not reduce sensitivity to ENF. Virus from patients experiencing viral load rebound exhibited reduced susceptibility to ENF and substitutions in gp41 aa 36-45. The most common substitutions observed on treatment were at positions 36, 38, 40, 42 and 43. On-treatment changes in the phenotypic susceptibility of virus isolates to ENF were generally associated with genotypic changes in aa 36-45. There was a relatively lower incidence of ENF resistance in patients with baseline sensitivity to more oral antiretrovirals in comparison to patients sensitive to fewer antiretrovirals.. These data identify the importance of HIV-1 gp41 aa 36-45 in the emergence of resistance to ENF.

Topics: Adult; DNA, Viral; Drug Resistance, Viral; Enfuvirtide; Genotype; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Middle Aged; Peptide Fragments; Phenotype

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.

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Injections, Subcutaneous; Male; Middle Aged; Peptide Fragments; Quality of Life; Reverse Transcriptase Inhibitors; Surveys and Questionnaires; Treatment Outcome

Interference with HIV entry into target cells provides a novel approach to the treatment of HIV infection. The inhibition of virus fusion with the co-receptor substrate seems the most specific and potentially best way to interfere with HIV infection and replication. The efficacy of the first compound available (enfuvirtide) is evident after the pre-registrative phase II and III studies showing also that the presence of anti gp 41 antibodies in the plasma of the treated patients does not interfere with drug activity. In the failing enfuvirtide treated patients resistant virus was detected in 7/7 after > one year of treatment with genotypic mutations in the HR env domain, however no interclass cross resistance was evidenced. Mutants selected in vivo demonstrated a slight reduction of replication capacity.

Topics: Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Enfuvirtide; Genes, env; HIV; HIV Antibodies; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Microbial Sensitivity Tests; Peptide Fragments; Virus Replication

The TORO 1 and TORO 2 clinical trials compared the efficacy and safety of enfuvirtide in combination with an optimized background antiretroviral regimen and optimized background regimen alone in HIV-1 infected patients. The patients had had previous treatment with each of the three classes of antiretroviral drugs and had a plasma level of HIV-1 RNA above 5000 copies/ml at baseline. They were randomly assigned in a 2:1 ratio to receive either enfuvirtide (90 mg subcutaneously twice daily) plus a background regimen optimized with the aid of resistance testing, or an optimized antiretroviral regimen alone (control group). Six hundred and sixty-one patients were enrolled in the enfuvirtide arm and 334 in the control group. The median baseline plasma HIV-1 RNA level was 5.2 log10 copies/ml in the enfuvirtide group and 5.1 log10 copies/ml in the control group. Patients had a median of 7 years of previous antiretroviral treatment. The optimized background regimen comprised a mean of 4 antiretroviral drugs in both groups. At week 48, the mean reduction in viral load was -1.48 log10 copies/ml in the enfuvirtide group, and -0.63 log10 copies/ml in the control group (difference = 0.846 log10 copies/ml, IC95%: -1.066; -0.626. p < 0.0001). The mean increase in the CD4+ cell count was significantly greater in the enfuvirtide group (91 cells/mm3) than in the control group (45 cells/mm3). Injection site reactions were the main reported adverse event which occurred in 98% of the enfuvirtide patients. Most had mild to moderate pain or discomfort not requiring analgesic or limiting usual activities.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Retroviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Injections, Subcutaneous; Male; Middle Aged; Peptide Fragments; Treatment Outcome; Viral Load

The T-20 vs. Optimized Regimen Only Study 1 (TORO 1) was a randomized, open-label, phase 3 study of enfuvirtide (T-20), a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor.. Patients from 48 sites in the United States, Canada, Mexico, and Brazil with at least six months of previous treatment with agents in three classes of antiretroviral drugs, resistance to drugs in these classes, or both, and with at least 5000 copies of HIV-1 RNA per milliliter of plasma were randomly assigned in a 2:1 ratio to receive enfuvirtide plus an optimized background regimen of three to five antiretroviral drugs or such a regimen alone (control group). The primary efficacy end point was the change in the plasma HIV-1 RNA level from base line to week 24.. A total of 501 patients underwent randomization, and 491 received at least one dose of study drug and had at least one measurement of plasma HIV-1 RNA after treatment began. The two groups were balanced in terms of the median base-line HIV-1 RNA level (5.2 log10 copies per milliliter in both groups), median CD4+ cell count (75.5 cells per cubic millimeter in the enfuvirtide group, and 87.0 cells per cubic millimeter in the control group), demographic characteristics, and previous antiretroviral therapy. At 24 weeks, the least-squares mean change from base line in the viral load (intention-to-treat, last observation carried forward) was a decrease of 1.696 log10 copies per milliliter in the enfuvirtide group, and a decrease of 0.764 log10 copies per milliliter in the control group (P<0.001). The mean increases in CD4+ cell count were 76 cells per cubic millimeter and 32 cells per cubic millimeter, respectively (P<0.001). Reactions at the site of the injections were reported by 98 percent of patients receiving enfuvirtide. There were more cases of pneumonia in the enfuvirtide group than in the control group.. The addition of enfuvirtide to an optimized antiretroviral regimen provided significant antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antiretroviral drugs and had multidrug-resistant HIV-1 infection.

Topics: Adult; Anti-HIV Agents; Brazil; CD4 Lymphocyte Count; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Injections, Subcutaneous; Male; North America; Patient Compliance; Peptide Fragments; RNA, Viral

The primary objective was to determine the long-term safety of the subcutaneous self-administration of enfuvirtide. Secondary objectives included the determination of enfuvirtide pharmacokinetics and antiviral activity and the immunological response to the enfuvirtide-containing regimen.. A multicenter 48-week uncontrolled open-label rollover study was conducted on 71 HIV-infected adults recruited from previous enfuvirtide clinical trials. Patients with extensive previous use of protease and reverse transcriptase inhibitors received a twice-daily dose of 50 mg enfuvirtide subcutaneously (45 mg deliverable) combined with two or more antiretroviral drugs selected for each individual, guided by resistance testing and previous treatment history.. The mean baseline plasma HIV-RNA level was 4.81 log(10) copies/ml and the mean CD4 cell count was 134.8 cells/microl. The majority (86.9%) of treatment-emergent adverse events were grade 2 or less in severity. Injection site reactions were common, but no patients discontinued treatment. A mean HIV-RNA change of -1.33 log(10) was achieved within 14 days of treatment initiation. At week 48, approximately one-third of all patients in the intent-to-treat population maintained significant suppression of plasma HIV RNA, with either less than 400 copies/ml or more than a 1.0 log(10) decline from baseline. The mean gain in absolute CD4 cell counts at 48 weeks was 84.9 cells/microl. Trough plasma concentrations of enfuvirtide were consistently higher than target concentrations.. Self-administration of enfuvirtide is not associated with unexpected toxicities for up to one year, and combined with oral antiretroviral drugs was associated with a significant decrease in HIV RNA and an increase in CD4 cell counts.

Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; RNA, Viral

The T-20 vs. Optimized Regimen Only Study 2 (TORO 2) compared the efficacy and safety of 24 weeks of treatment with the fusion inhibitor enfuvirtide in combination with an optimized background antiretroviral regimen with the efficacy and safety of the optimized background regimen alone.. The patients had previous treatment with each of the three classes of antiretroviral drugs, documented resistance to each class, or both and a plasma level of human immunodeficiency virus type 1 (HIV-1) RNA of at least 5000 copies per milliliter. They were randomly assigned in a 2:1 ratio to receive either enfuvirtide (90 mg twice daily) plus a background regimen optimized with the aid of resistance testing (enfuvirtide group) or the background regimen alone (control group).. Of the 512 patients who underwent randomization, 335 in the enfuvirtide group and 169 in the control group received at least one dose of study medication and had at least one follow-up measurement of plasma HIV-1 RNA. The median base-line plasma HIV-1 RNA level was 5.1 log10 copies per milliliter in both groups. The median CD4+ cell count was 98.0 cells per cubic millimeter in the enfuvirtide group and 101.5 cells per cubic millimeter in the control group. Patients had a median of seven years of previous treatment and had received a median of 12 antiretroviral drugs. The background regimen comprised a mean of four antiretroviral drugs in both groups. At 24 weeks, the least-squares mean change from base line in the plasma viral load (intention-to-treat, last observation carried forward) was a decrease of 1.429 log10 copies per milliliter in the enfuvirtide group and a decrease of 0.648 log10 copies per milliliter in the control group, a difference of 0.781 log10 copies per milliliter (P<0.001). The mean increase in the CD4+ cell count was greater in the enfuvirtide group (65.5 cells per cubic millimeter) than in the control group (38.0 cells per cubic millimeter, P=0.02).. The addition of enfuvirtide to an optimized background regimen provided significant viral suppression and immunologic benefit over a 24-week period in HIV-1-infected patients who had previously received multiple antiretroviral drugs.

Topics: Adult; Anti-HIV Agents; Australia; CD4 Lymphocyte Count; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; Europe; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Injections, Subcutaneous; Male; Patient Compliance; Peptide Fragments; RNA, Viral

Enfuvirtide is the first in a new class of antiretrovirals (ARVs), the fusion inhibitors, and the first ARV to be administered by subcutaneous (s.c.) injection.. The primary objective of this study was to determine the steady-state pharmacokinetics and relative bioavailability of enfuvirtide following sc injection at three separate anatomical sites: abdomen (A), thigh (B) and arm (C).. A single-center, open-label, multiple-dose, three-way randomized, crossover study. Twelve HIV-1-infected adults were recruited from three ongoing Phase II enfuvirtide clinical trials and randomized into three groups. Each group continued to receive s.c. injection of enfuvirtide, at a dose of 90 mg twice daily (bid), according to one of three treatment sequences: ABC, BCA or CAB; over three consecutive periods of approximately 7 days each. Plasma concentrations of enfuvirtide and its metabolite (Ro 50-6343) were measured using a validated liquid chromatography-tandem mass spectrometry method.. The relative bioavailability of enfuvirtide, based on AUC12h and abdomen as a reference site, was 101% for thigh and 117% for arm. The AUC12h of Ro 50-6343 ranged from 14 to 16% of that for enfuvirtide. Although injection site reactions (ISRs) were common, the overall grading (based on pain or discomfort) of all reported ISRs was Grade 1 (mild). The incidence of ISRs varied according to the site of injection, as did the signs and symptoms associated with them. No patient required treatment for an ISR.. Comparability among the three injection sites, in terms of both absorption and the ISR profile, allows HIV-1-infected patients the freedom to choose and to rotate, if necessary, the site of enfuvirtide injection among the three anatomical sites.

Topics: Dose-Response Relationship, Drug; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Injections, Subcutaneous; Male; Middle Aged; Peptide Fragments; Safety

Enfuvirtide is a novel antiretroviral that blocks HIV-1 cell fusion and viral entry. This Phase II, controlled, open-label, randomized, multicentre dose-ranging trial explored the safety, antiviral activity and pharmacokinetics of enfuvirtide, administered by subcutaneous (s.c.) injection, in 71 HIV-1-infected, protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive adults for 48 weeks. Study participants were randomized to receive enfuvirtide at a deliverable dose of 45, 67.5 or 90 mg twice daily; the 45 mg twice daily dose required 2 injections/day, while the higher doses required 4 injections/day. A background oral antiretroviral (ARV) regimen of abacavir (300 mg twice daily), amprenavir (1200 mg twice daily), ritonavir (200 mg twice daily) and efavirenz (600 mg once daily) was provided with enfuvirtide. A control group received the background ARV regimen alone. All potential participants underwent an HIV genotype at screen to ensure a homogenous population and to exclude patients with evidence of genotypic resistance to NNRTIs. Overall, the tolerability of the combination of abacavir, amprenavir, ritonavir, efavirenz and enfuvirtide was generally comparable to control through 48 weeks. No enfuvirtide dose-dependent adverse events (AEs) were observed across treatment groups. Injection site reactions (ISRs) occurred at least once in 68.5% of the enfuvirtide-treated population, and most ISRs were mild to moderate in severity, with no apparent dose relationship. Excluding ISRs, the most common treatment-emergent AEs were nausea, diarrhoea, dizziness and fatigue; with no clinically significant differences in the incidence of AEs observed between the control and enfuvirtide groups. Each treatment group benefited from ARV therapy, with a trend of increasing antiviral and immunological activity associated with increasing enfuvirtide dose. At 48 weeks, the median HIV-1 RNA change from baseline for the ITT population was -2.24 log10 copies/ml for the combined enfuvirtide groups compared with -1.87 log10 copies/ml for the control group. In addition, 54.9% of patients in the enfuvirtide group achieved HIV-1 RNA < or = 400 copies/ml versus 36.8% of patients in the control group. These results indicate that enfuvirtide has a favourable safety profile and is a promising new antiviral agent for HIV-infected patients who have been on previously failing ARV regimens.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Enfuvirtide; Female; Furans; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Peptide Fragments; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load

The primary objective was to determine whether rifampicin influences the pharmacokinetics of enfuvirtide in HIV-1-infected patients. In a single-center, open-label, one-sequence crossover, clinical pharmacology study, 12 HIV-1-infected adults received enfuvirtide (90 mg, twice daily) on days 1 to 3 and days 11 to 13 (morning dose only on days 3 and 13) and rifampicin (600 mg, once daily) from days 4 to 13. Plasma concentrations were measured for enfuvirtide and its metabolite (days 3 and 13) and rifampicin (day 13 only). The ratios of least squares means (LSM) and 90% confidence intervals for enfuvirtide and enfuvirtide metabolite pharmacokinetic parameters (AUC12h, Cmax, Ctrough) were estimated in the presence and absence of rifampicin. Treatments were compared using an analysis of variance for natural log-transformed variables, with factors patient and treatment. Efficacy and safety were also monitored. Steady-state rifampicin had no appreciable effect on any of the pharmacokinetic parameters assessed for either enfuvirtide or its metabolite. The ratio of LSM for AUC12h, Cmax, and Ctrough for enfuvirtide was 97.5%, 103%, and 84.9%, respectively, and 108%, 112%, and 92.9%, for the enfuvirtide metabolite. Rifampicin did not affect the t1/2 of enfuvirtide or its metabolite. There were no unexpected effects of rifampicin on the short-term antiviral effect or safety of the administered antiretroviral treatment. The pharmacokinetics of enfuvirtide are not induced by a 10-day pretreatment with rifampicin.

Topics: Adult; Area Under Curve; Drug Interactions; Enfuvirtide; Enzyme Inhibitors; Female; Half-Life; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Rifampin

The present study investigated the effect of enfuvirtide cross-reactive glycoprotein 41 (gp41) antibody on the efficacy or safety of enfuvirtide in patients participating in 1 of 2 24-week phase 3 clinical trials (T-20 vs. optimized regimen only [TORO] 1 and TORO 2). Serum samples from human immunodeficiency virus-infected patients receiving enfuvirtide plus optimized background (OB) and from patients receiving OB only were evaluated for enfuvirtide cross-reactive gp41 antibodies. Most patients had detectable levels of antibody at baseline; 78% of patients treated with enfuvirtide plus OB had a > or =30% decrease in level of antibody, compared with 43% of patients treated with OB only. Baseline antibody status did not influence virological responses to enfuvirtide-containing treatment. Favorable virological responses were more common among patients who experienced a > or =30% decrease from baseline than among those who experienced either an increase or a lesser decrease. A decrease in virus load correlated with a decrease in level of antibody. Safety was unaffected by the presence of positive antibody at any time point or change in level of antibody. There was no evidence that enfuvirtide cross-reactive gp41 antibody affects the efficacy or safety of enfuvirtide.

Topics: Adolescent; Adult; Cross Reactions; Drug Hypersensitivity; Enfuvirtide; HIV Antibodies; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Injections, Subcutaneous; Pain; Peptide Fragments; RNA, Viral; Skin; Viral Load

Enfuvirtide (T-20) is the first of a novel class of human immunodeficiency virus (HIV) drugs that block gp41-mediated viral fusion to host cells. The objectives of this study were to develop a structural pharmacokinetic model that would adequately characterize the absorption and disposition of enfuvirtide pharmacokinetics after both intravenous and subcutaneous administration and to evaluate the dose proportionality of enfuvirtide pharmacokinetic parameters at a subcutaneous dose higher than that currently used in phase III studies.. Twelve patients with HIV infection received 4 single doses of enfuvirtide separated by a 1-week washout period in an open-label, randomized, 4-way crossover fashion. The doses studied were 90 mg (intravenous) and 45 mg, 90 mg, and 180 mg (subcutaneous). Serial blood samples were collected up to 48 hours after each dose. Plasma enfuvirtide concentrations were measured with use of a validated liquid chromatography-tandem mass spectrometry method.. Enfuvirtide plasma concentration-time data after subcutaneous administration were well described by an inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment. The model-derived mean pharmacokinetic parameters (+/-SD) were volume of distribution of the central compartment (3.8 +/- 0.8 L), volume of distribution of the peripheral compartment (1.7 +/- 0.6 L), total clearance (1.44 +/- 0.30 L/h), intercompartmental distribution (2.3 +/- 1.1 L/h), bioavailability (89% +/- 11%), and mean absorption time (7.26 hours, 8.65 hours, and 9.79 hours for the 45-mg, 90-mg, and 180-mg dose groups, respectively). The terminal half-life increased from 3.46 to 4.35 hours for the subcutaneous dose range from 45 to 180 mg.. An inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment was appropriate to describe complex absorption and disposition kinetics of enfuvirtide plasma concentration-time data after subcutaneous administration to patients with HIV infection. Enfuvirtide was nearly completely absorbed from subcutaneous depot, and pharmacokinetic parameters were linear up to a dose of 180 mg in this study.

Topics: Absorption; Adult; Algorithms; Anti-HIV Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; Humans; Injections, Subcutaneous; Male; Middle Aged; Models, Biological; Normal Distribution; Peptide Fragments

T-20, a synthetic peptide corresponding to a region of the transmembrane subunit of the HIV-1 envelope protein, blocks cell fusion and viral entry at concentrations of less than 2 ng/ml in vitro. We administered intravenous T-20 (monotherapy) for 14 days to sixteen HIV-infected adults in four dose groups (3, 10, 30 and 100 mg twice daily). There were significant, dose-related declines in plasma HIV RNA in all subjects who received higher dose levels. All four subjects receiving 100 mg twice daily had a decline in plasma HIV RNA to less than 500 copies/ml, by bDNA assay. A sensitive RT-PCR assay (detection threshold 40 copies/ml) demonstrated that, although undetectable levels were not achieved in the 14-day dosing period, there was a 1.96 log10 median decline in plasma HIV RNA in these subjects. This study provides proof-of-concept that viral entry can be successfully blocked in vivo. Short-term administration of T-20 seems safe and provides potent inhibition of HIV replication comparable to anti-retroviral regimens approved at present.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dose-Response Relationship, Drug; Enfuvirtide; Half-Life; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Metabolic Clearance Rate; Peptide Fragments; Virus Replication

Large peptide biosynthesis is a valuable alternative to conventional chemical synthesis. Enfuvirtide, the largest therapeutic peptide used in HIV infection treatment, was synthesized in our thermostable chaperone-based peptide biosynthesis system and evaluated for peptide quality as well as the profile of process-related impurities. Host cell proteins (HCPs) and BrCN cleavage-modified peptides were evaluated by LC-MS in intermediate. Cleavage modifications during the reaction were assessed after LC-MS maps were aligned by simple in-house algorithm and formylation/oxidation levels were estimated. Circular dichroism spectra of the obtained enfuvirtide were compared to the those of the chemically- synthesized standard product. Final-product endotoxin and HCPs content were assessed resulting 1.06 EU/mg and 5.58 ppm respectively. Peptide therapeutic activity was measured using the MT-4 cells HIV infection-inhibition model. The biosynthetic peptide IC50 was 0.0453 μM while the standard one had 0.0180 μM. Non-acylated C-terminus was proposed as a cause of IC50 and CD spectra difference. Otherwise, the peptide has met all the requirements of the original chemically synthesized enfuvirtide in the cell-culture and in vivo experiments.

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments; Peptides

Human immunodeficiency virus (HIV) increasing molecular diversity and emergence of drug resistant mutants remain a major concern in China. Enfuvirtide (ENF/T-20) is the first entry inhibitor used in patients failing highly active antiretroviral therapy (HAART). However, data on HIV-1 gp41genetic diversity and primary ENF resistance-associated mutations among treatment-naïve patients in China is limited. The objective was to identify molecular diversity and ENF resistance patterns of HIV-1 in southern China, using envelope (env) gp41 sequences and bioinformatics tools, which may help optimize antiretroviral therapy.. From November 2018 to January 2019, 439 blood plasma samples from ENF-naïve patients were collected from Shenzhen, Wuhan and Chongqing, of which 396 HIV env regions were sequenced and subtyped, and were performed the analysis of drug resistance-associated mutations (DRMs).. The main subtypes were circulating recombinant form (CRF) 01_AE (30.6 %) and CRF07_BC (48.7 %). CRF55_01B had been the fourth subtype in the study, and many rare CRFs were observed. Notably, CRF02_AG and CRF_BF strains typically found in Africa and US respectively were identified amongst Chinese patients. Known DRMs were detected in 27.5 % (109/396) of ENF treatment-naïve patients. One major DRM (L44 M), many secondary DRMs (including N126 K, E137 K, S138A), and lots of polymorphisms were found in the study, which have been proved to elevate resistance to ENF.. HIV-1 molecular diversity was observed in the study, which indicating that HIV-1 variability is becoming increasingly complex in southern China. A diverse set of primary DRMs discovered in this study described the serious threat to ART, which reminds us the urgent need of timely surveillance of HIV-1 viral diversity and drug resistance in China.

Topics: Anti-HIV Agents; China; Drug Resistance, Viral; Enfuvirtide; Genetic Variation; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Mutation; Phylogeny

Topics: Amyloidosis, Familial; Enfuvirtide; HIV Infections; Humans; Skin Diseases, Genetic

The clinical application of HIV fusion inhibitor, enfuvirtide (T20), was limited mainly because of its short half-life. Here we designed and synthesized two PEGylated C34 peptides, PEG2kC34 and PEG5kC34, with the PEG chain length of 2 and 5 kDa, respectively, and evaluated their anti-HIV-1 activity and mechanisms of action. We found that these two PEGylated peptides could bind to the HIV-1 peptide N36 to form high affinity complexes with high α-helicity. The peptides PEG2kC34 and PEG5kC34 effectively inhibited HIV-1 Env-mediated cell-cell fusion with an effective concentration for 50% inhibition (EC

Topics: Amino Acid Sequence; Animals; Cell Line; Circular Dichroism; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Membrane Fusion; Mutation; Peptide Fragments; Polyethylene Glycols; Protein Binding; Protein Conformation, alpha-Helical; Rats; Virus Replication

Combination antiretroviral therapy (cART) dramatically improves survival of HIV-infected patients, but lifelong treatment can ultimately result in cumulative toxicities and drug resistance, thus necessitating the development of new drugs with significantly improved pharmaceutical profiles. We recently found that the fusion inhibitor T-20 (enfuvirtide)-based lipopeptides possess dramatically increased anti-HIV activity. Herein, a group of novel lipopeptides were designed with different lengths of fatty acids, identifying a stearic acid-modified lipopeptide (LP-80) with the most potent anti-HIV activity. It inhibited a large panel of divergent HIV subtypes with a mean IC50 in the extremely low picomolar range, being > 5,300-fold more active than T-20 and the neutralizing antibody VRC01. It also sustained the potent activity against T-20-resistant mutants and exhibited very high therapeutic selectivity index. Pharmacokinetics of LP-80 in rats and monkeys verified its potent and long-acting anti-HIV activity. In the monkey, subcutaneous administration of 3 mg/kg LP-80 yielded serum concentrations of 1,147 ng/ml after injection 72 h and 9 ng/ml after injection 168 h (7 days), equivalent to 42,062- and 330-fold higher than the measured IC50 value. In SHIV infected rhesus macaques, a single low-dose LP-80 (3 mg/kg) sharply reduced viral loads to below the limitation of detection, and twice-weekly monotherapy could maintain long-term viral suppression.

Topics: Animals; Anti-Retroviral Agents; Antibodies, Neutralizing; Drug Resistance, Viral; Enfuvirtide; HEK293 Cells; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Lipopeptides; Macaca mulatta; Male; Rats; Rats, Sprague-Dawley; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Viral Load; Virus Internalization

Drugs that block HIV-1 entry are relatively limited. Enfuvirtide is a 36-residue synthetic peptide that targets gp41 and blocks viral fusion. However, Enfuvirtide-resistant HIV has been reported, and this peptide drug requires daily injection. Previously, we have reported helix-grafted display proteins, consisting of HIV-1 gp41 C-peptide helix grafted onto Pleckstrin Homology domains. Some of these biologics inhibit HIV-1 entry with relatively modest and varied potency (IC

Topics: Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptides; Protein Conformation, alpha-Helical; Protein Engineering; Virus Internalization

HIV therapy with anti-retroviral drugs is limited by the poor exposure of viral reservoirs, such as lymphoid tissue, to these small molecule drugs. We therefore investigated the effect of PEGylation on the anti-retroviral activity and subcutaneous lymphatic pharmacokinetics of the peptide-based fusion inhibitor enfuvirtide in thoracic lymph duct cannulated rats. Both the peptide and the PEG were quantified in plasma and lymph via ELISA. Conjugation to a single 5 kDa linear PEG decreased anti-HIV activity three-fold compared to enfuvirtide. Whilst plasma and lymphatic exposure to peptide mass was moderately increased, the loss of anti-viral activity led to an overall decrease in exposure to enfuvirtide activity. A 20 kDa 4-arm branched PEG conjugated with an average of two enfuvirtide peptides decreased peptide activity by six-fold. Plasma and lymph exposure to enfuvirtide, however, increased significantly such that anti-viral activity was increased two- and six-fold respectively. The results suggest that a multi-enfuvirtide-PEG complex may optimally enhance the anti-retroviral activity of the peptide in plasma and lymph.

Topics: Animals; Cell Line; Enfuvirtide; Enzyme-Linked Immunosorbent Assay; HIV; HIV Fusion Inhibitors; HIV Infections; Humans; Lymph; Male; Polyethylene Glycols; Rats; Rats, Sprague-Dawley

HIV infection requires lifelong treatment with multiple antiretroviral drugs in a combination, which ultimately causes cumulative toxicities and drug resistance, thus necessitating the development of novel antiviral agents. We recently found that enfuvirtide (T-20)-based lipopeptides conjugated with fatty acids have dramatically increased

Topics: Animals; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Cell Line; Drug Design; Drug Resistance, Viral; Enfuvirtide; HEK293 Cells; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; HIV-2; Humans; Lipopeptides; Macaca mulatta; Membrane Fusion; Peptide Fragments; Virus Internalization

Identifying drug resistance mutations is important for the clinical use of antivirals and can help define both a drug's mechanism of action and the mechanistic basis of resistance. Resistance mutations are often identified one-at-a-time by studying viral evolution within treated patients or during viral growth in the presence of a drug in cell culture. Such approaches have previously mapped resistance to enfuvirtide, the only clinically approved HIV-1 fusion inhibitor, to enfuvirtide's binding site in the N-terminal heptad repeat (NHR) of the Envelope (Env) transmembrane domain as well as a limited number of allosteric sites. Here, we sought to better delineate the genotypic determinants of resistance throughout Env. We used deep mutational scanning to quantify the effect of all single-amino-acid mutations to the subtype A BG505 Env on resistance to enfuvirtide. We identified both previously characterized and numerous novel resistance mutations in the NHR. Additional resistance mutations clustered in other regions of Env conformational intermediates, suggesting they may act during different fusion steps by altering fusion kinetics and/or exposure of the enfuvirtide binding site. This complete map of resistance sheds light on the diverse mechanisms of enfuvirtide resistance and highlights the utility of using deep mutational scanning to comprehensively map potential drug resistance mutations.

Topics: Anti-Retroviral Agents; Drug Resistance, Viral; Enfuvirtide; Genotype; High-Throughput Nucleotide Sequencing; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Models, Molecular; Mutation; Viral Fusion Proteins

Fusion inhibitors are antiretroviral (ARV) drugs that prevent HIV-1 entry into host cells. Enfuvirtide (ENF) is the only ARV drug marketed in this class and, like other HIV drugs, it has been associated with the emergence and selection of therapeutic-resistant HIV-1 strains. The aims of this work were to develop a computational tool capable of identifying and classifying mutations associated with resistance to Enfuvirtide and to evaluate the prevalence of these mutations among the HIV-1 sequences deposited in public databases. The HIVfird (HIV-1 fusion inhibitor resistance detector) was developed using the PHP programming language, using 30 DNA bases obtained from the HIV-1 HXB2 gp41 protein as a reference. To assess the level of resistance in HIV-1 populations, sequences were retrieved from the Los Alamos National Laboratory (LANL) database. The HIVfird is hosted at www.hivfird.ics.ufba.br, fully functional and available for public use. Twenty-five amino acid substitutions and 15 combinations were found to be associated with some level of resistance to ENF. These mutations are located at positions 36-45 of gp41, with 36, 38, 43, and 44 having the greatest diversity and frequency of variations associated with drug resistance. Resistance mutations were found in 3.16% and 4.67% of the circulating HIV-1 isolates in the world and Brazil, respectively. Subtype B showed a significantly higher ENF resistance rate (4.9%) compared to other genetic forms, while subtype C presented the lowest rate (0.9%). We present here HIVfird, an online tool that might assist in the therapeutic management of HIV-1 patients with multiple drug failure and in population-based analysis of drug resistance.

Topics: Amino Acid Sequence; Amino Acid Substitution; Base Sequence; Databases, Genetic; DNA Mutational Analysis; DNA, Viral; Drug Resistance, Viral; Enfuvirtide; Global Health; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Internet; Mutation; Mutation, Missense; Sequence Alignment; Sequence Homology, Nucleic Acid; Software

During HIV infection, fusion of the viral and cellular membranes is dependent on folding of the gp41 trimer into a six-helix bundle. Fusion inhibitors, such as the antiretroviral Enfuvirtide (T20), interfere with the formation of the gp41 six-helix bundle. Recent in vitro studies reveal that the gp41 immunodominant region one targeting antibody 3D6 can block T20 interference, but the clinical and pathophysiologic significance of this finding is unclear.. We have previously characterized a number of antibodies that target conformational epitopes on gp41and herein characterized their ability to interfere with T20 in multiple assays and assess their prevalence in HIV infected subjects.. The T20 interference by antibody 3D6 was confirmed in a CHO-HXB2 envelope/ HeLaT4+ cell culture assay. Antibodies that target an immunodominant region one epitope, as well as a gp41 discontinuous epitope, also interfered in this assay, however, not all antibodies that targeted these epitopes showed T20 interference. This response was not due to the direct binding of T20 by the antibodies and could not be replicated utilizing TZM-bl and HL2/3 cells. Notably, serum competition studies on a panel of HIV subjects demonstrate that these conformational targeting antibodies are common in the HIV population.. The relatively common nature of antibodies targeting these epitopes, the disparate in vitro results, and lack of reported clinical failures ascribed to such antibodies leads us to conclude that antibody interference of T20 is likely not clinically relevant. However, this warrants continued consideration with the advancement of other fusion inhibitors.

Topics: Animals; Cell Line; Drug Interactions; Enfuvirtide; HIV Antibodies; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans

Most peptide drugs have short half-lives, necessitating frequent injections that may induce skin sensitivity reactions; therefore, versatile prolonged-release delivery platforms are urgently needed. Here, we focused on an oxidatively and thermally responsive recombinant elastin-like polypeptide with periodic cysteine residues (cELP), which can rapidly and reversibly form a disulfide cross-linked network in which peptide can be physically incorporated. As a model for proof of concept, we used enfuvirtide, an antiretroviral fusion-inhibitor peptide approved for treatment of human immunodeficiency virus (HIV) infection. cELP was mixed with enfuvirtide and a small amount of hydrogen peroxide (to promote cross-linking), and the soluble mixture was injected subcutaneously. The oxidative cross-linking generates a network structure, causing the mixture to form a hydrogel in situ that serves as an enfuvirtide depot. We fabricated a series of enfuvirtide-containing hydrogels and examined their stability, enfuvirtide-releasing profile and anti-HIV potency in vitro. Among them, hydrophobic cELP hydrogel provided effective concentrations of enfuvirtide in blood of rats for up to 8 h, and the initial concentration peak was suppressed compared with that after injection of enfuvirtide alone. cELP hydrogels should be readily adaptable as platforms to provide effective depot systems for delivery of other anti-HIV peptides besides enfuvirtide.. In this paper, we present an anti-HIV peptide delivery system using oxidatively and thermally responsive polypeptides that contain multiple periodic cysteine residues as an injectable biomaterial capable of in situ self-gelation, and we demonstrate its utility as an injectable depot capable of sustained release of anti-HIV peptides. The novelty of this work stems from the platform employed to provide the depot encapsulating the peptide drugs (without chemical conjugation), which consists of rationally designed, genetically engineered polypeptides that enable the release rate of the peptide drugs to be precisely controlled.

Topics: Animals; Cell Line; Cross-Linking Reagents; Drug Implants; Elastin; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Hydrogels; Hydrogen Peroxide; Male; Peptide Fragments; Rats; Rats, Sprague-Dawley; Recombinant Proteins

HIV-1 gp41 plays a key role in viral entry. The insertion of Thr at position 4 and Met/Val/Phe substitutions at position 7 are frequently observed in the fusion peptide (FP) motif of gp41 without major enfuvirtide resistance associated with mutation in heptad repeats 1/2 (HR1/2) of HIV-1 isolates from Korean patients. Here, the influence of these mutations on their biological function was evaluated by employing HIV-1 variants with mutant FPs as shown previously and with recombinant HIV-1 using the env genes of 20 HIV-1 isolates from Korean patients. In an infectivity assay, all FP mutants showed lower infectivity than the wild-type NL4-3. In particular, the substitutions at position 7 led to much greater reductions in infectivity than the insertions at position 4. Nevertheless, the replication kinetics of most mutants were similar to those of the wild type, except that the FP mutants with an Ile insertion at position 4 and a Phe substitution at position 7 showed reduced replication. Moreover, most point mutants showed lower IC50 values for enfuvirtide than the wild type, whereas the L7M substitution resulted in a slightly increased IC50 value. The infectivity using the HIV-1 env recombinant viruses decreased in 14 cases but increased slightly in six cases compared with the wild type. Most recombinants were more susceptible to enfuvirtide than the wild type, except for three recombinants that showed slight resistance. Our findings may help to explain the potential mechanisms corresponding to the natural polymorphism of gp41 and to predict the efficiency of enfuvirtide in treatment of HIV-1-infected patients in Korea.

Topics: Adult; Amino Acid Substitution; Anti-HIV Agents; Drug Resistance, Viral; Enfuvirtide; Female; Genes, env; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Middle Aged; Mutagenesis, Insertional; Mutation; Peptide Fragments; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Republic of Korea; Virulence; Virus Replication; Young Adult

Case description To evaluate whether continuous intravenous (i.v.) administration of enfuvirtide (T20) could be a suitable alternative to subcutaneous (s.c.) administration of T20 in a patient with extensively drug-resistant HIV experiencing difficulties administering T20 subcutaneously. T20 was administered to a patient through 100 mL cassettes once daily via a CADD. Plasma samples were drawn and the pharmacokinetic profile compared to that of s.c. twice daily administration of T20. Also, viral replication and CD4+ count were monitored over a period of 9 months for this study. Continuous i.v. administration of T20 resulted in significantly higher T20 plasma levels compared to s.c. administration, continued viral suppression, a rise in CD4+ count and strong patient preference over s.c. administration. Conclusion This method of T20 administration may be a suitable alternative for selected patients who are not able to tolerate it when given subcutaneously. It may even be considered a priori in selected patients with extensive viral resistance who are unable or unwilling to inject T20 subcutaneously.

Topics: Aged; CD4 Antigens; Drug Resistance, Multiple; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Infections; Humans; Infusions, Intravenous; Injections, Subcutaneous; Patient Preference; Peptide Fragments

Enfuvirtide (ENF) is a clinically used peptide drug for the treatment of HIV infections, but its poor pharmacokinetic profile (T1/2 = 1.5 h in rats) and low aqueous solubility make the therapy expensive and inconvenience. In this study, we present a simple and practical strategy to address these problems by conjugating ENF with polyethylene glycol (PEG). Site-specific attachment of a 2 kDa PEG at the N-terminus of ENF resulted in an ENF-PEG (EP) conjugate with high solubility (≥3 mg/mL) and long half-life in rats (T1/2 = 16.1 h). This conjugate showed similar antiviral activity to ENF against various primary HIV-1 isolates (EC50 = 6-91 nM). Mechanistic studies suggested the sources of the antiviral potency. The conjugate bound to a functional domain of the HIV gp41 protein in a helical conformation with high affinity (Kd = 307 nM), thereby inhibiting the gp41-mediated fusion of viral and host-cell membranes. As PEG conjugation has advanced many bioactive proteins and peptides into clinical applications, the EP conjugate described here represents a potential new treatment for HIV infections that may address the unmet medical needs associated with the current ENF therapy.

Topics: Animals; Antiviral Agents; Enfuvirtide; Half-Life; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Peptide Fragments; Polyethylene Glycols; Rats; Solubility

Enfuvirtide (T20), is the first HIV fusion inhibitor approved for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, its clinical application is limited because of short half-life, drug resistance and cross-reactivity with the preexisting antibodies in HIV-infected patients. Using an artificial peptide strategy, we designed a peptide with non-native protein sequence, AP3, which exhibited potent antiviral activity against a broad spectrum of HIV-1 strains, including those resistant to T20, and had remarkably longer in vivo half-life than T20. While the preexisting antibodies in HIV-infected patients significantly suppressed T20's antiviral activity, these antibodies neither recognized AP3, nor attenuated its anti-HIV-1 activity. Structurally different from T20, AP3 could fold into single-helix and interact with gp41 NHR. The two residues, Met and Thr, at the N-terminus of AP3 form a hook-like structure to stabilize interaction between AP3 and NHR helices. Therefore, AP3 has potential for further development as a new HIV fusion inhibitor with improved antiviral efficacy, resistance profile and pharmacological properties over enfuvirtide. Meanwhile, this study highlighted the advantages of artificially designed peptides, and confirmed that this strategy could be used in developing artificial peptide-based viral fusion inhibitors against HIV and other enveloped viruses.

Topics: Amino Acid Sequence; Animals; Biophysical Phenomena; Crystallography, X-Ray; Endopeptidase K; Enfuvirtide; HIV Antibodies; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Liver; Male; Models, Molecular; Molecular Sequence Data; Peptide Fragments; Peptides; Protein Structure, Secondary; Proteolysis; Rats, Sprague-Dawley

The effectiveness of switching from enfuvirtide to raltegravir in HIV-1-infected patients on a suppressive antiretroviral regimen has been poorly studied in the clinical practice of developing countries. We conducted a multicenter retrospective cohort study in HIV-1-infected, multidrug-experienced adults (≥18 years old) with plasma HIV-1-RNA <400 copies/ml for at least 4 months on an enfuvirtide-containing therapy between 2005 and 2010, in whom the attending physician switched from enfuvirtide to raltegravir. Effectiveness endpoints were measured at week 48 after switch. Analyses were conducted on an intent-to-treat basis and two strategies for handling missing outcome data were used (hereafter, strategies 1 and 2). Overall, 87 patients were eligible for analysis. At baseline, the median CD4(+) T cell count was 400 cells/μl and 91.9% of patients had <50 HIV-1-RNA copies/ml. At week 48, the proportions of patients with plasma HIV-1-RNA <50 and <400 copies/ml were, respectively, 86.2% (95% CI=77.1; 92.7%) and 88.5% (95% CI=79.9; 94.3%) (strategies 1 and 2) and 89.7% (95% CI=81.3; 95.2%) and 90.8% (95% CI=82.7; 95.9%) (strategies 1 and 2). This was a -10.3% (95% CI=-2.8; -17.9%) and -9.2% (95% CI=-2; -16.4%) difference from baseline in the proportion of patients with plasma HIV-1-RNA <400 copies/ml. The median increase in CD4(+) T cell counts was 41 and 64 cells/μl (p<0.001) (strategies 1 and 2). No patient withdrew raltegravir or developed opportunistic infections, but one was diagnosed with HIV-related dementia. In conclusion, switching from enfuvirtide to raltegravir in patients on a virologically suppressive regimen is an effective strategy even in a Brazilian clinical setting.

Topics: Adolescent; Adult; Anti-HIV Agents; Brazil; CD4 Lymphocyte Count; Cohort Studies; Drug Resistance, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load; Young Adult

We assessed the immunovirological response to antiretroviral regimens containing maraviroc in HIV-infected viremic patients with viral tropism predicted by different assays. We selected antiretroviral treatment-experienced HIV-1-infected patients initiating regimens containing maraviroc after different phenotypic or genotypic viral tropism assays, with at least one HIV-1 RNA determination during follow-up. Survival analysis was employed to assess the virological response as time to HIV-1 RNA <50 copies/ml and immunological response as time to a CD4 cell count increase of ≥ 100/μl from baseline. Predictors of these outcomes were analyzed by multivariate Cox regression models. In 191 treatments with maraviroc, virological response was achieved in 65.4% and the response was modestly influenced by the baseline viral load and concomitant drug activity but not influenced by the type of tropism assay employed. Immunological response was achieved in 58.1%; independent predictors were baseline HIV-1 RNA (per log10 higher: HR 1.29, 95% CI 1.05-1.60) and concomitant therapy with enfuvirtide (HR 2.05, 0.96-4.39) but not tropism assay results. Of 17 patients with baseline R5-tropic virus and available tropism results while viremic during follow-up on maraviroc, seven (41%) showed a tropism switch to non-R5 virus. A significant proportion of experienced patients treated with regimens containing maraviroc achieved virological response. The tropism test type used was not associated with immunovirological response and concomitant treatment with enfuvirtide increased the chance of immunological response. More than half of virological failures with maraviroc were not accompanied by tropism switch.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CCR5 Receptor Antagonists; CD4 Lymphocyte Count; Cyclohexanes; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Maraviroc; Middle Aged; Peptide Fragments; Retrospective Studies; RNA, Viral; Survival; Triazoles; Viral Load; Viral Tropism

The selective pressure of antiretroviral drugs (ARVs) targeting HIV-1 pol can promote drug resistance mutations in other genomic regions, such as env. Drug resistance among women should be monitored to avoid horizontal and mother-to-child transmission. To describe natural resistance to T-20 (enfuvirtide), gp41 env polymorphisms, mutations in pol and HIV-1 subtypes, 124 pregnant women were recruited. For 98 patients, the gp41 env, protease (PR) and reverse transcriptase (RT) fragments were sequenced. The patients were ARV naïve (n = 30), taking mother-to-child transmission prophylaxis (n = 50), or being treated with highly active ARV therapy/HAART (n = 18). The Stanford and IAS/USA databases and other sources were used to analyze PR/RT, gp41 env resistance mutations. The HIV-1 genetic diversity was analyzed by REGA/phylogenetic analyses. The patients' median age was 25 years (range, 16-42), 18.4% had AIDS. The frequency of natural resistance to T-20 (N42D, L44M, and R46M-low-impact mutations) was 6.1% (6/98); 20.4% (20/98) had compensatory mutations in HR2. The prevalence of transmitted drug resistance in the pol was 13.3% (4/30), and the prevalence of secondary drug resistance was 33.3% (6/18). Two patients were infected with multidrug resistant/MDR viruses. The analysis of HIV-1 subtypes (PR/RT/gp41) revealed that 61.2% (60/98) were subtype B, 12.2% (12/98) were subtype C, 4.1% (4/98) were subtype F1, and 22.4% (22/98) were possible recombinants (BF1 = 20.4%; BC = 2%). Natural resistance to T-20 was not associated with pol resistance or previous ARV use. The high rate of secondary resistance, including MDR, indicates that the number of women that may need T-20 salvage therapy may be higher than anticipated.

Topics: Adolescent; Adult; Anti-HIV Agents; Brazil; Drug Resistance, Viral; Enfuvirtide; Female; Genetic Variation; Genotype; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation, Missense; Peptide Fragments; pol Gene Products, Human Immunodeficiency Virus; Pregnancy; Pregnancy Complications, Infectious; Prevalence; Sequence Analysis, DNA; Young Adult

Enfuvirtide was the first fusion inhibitor approved by the Food and Drug Administration (FDA) in 2003 for HIV-1 infection in treatment-experienced patient. It is the first approved antiviral agent to attack the HIV life cycle in its early stages. For HIV fusion to occur, the HR1 and HR2 domains in the gp41 region need to interact. Enfuvirtide is a synthetic peptide that corresponds to 36 amino acids of the HR2, which competitively binds to HR1 inhibiting the interaction with the HR2 domain thus preventing fusogenic conformation and inhibiting viral entry into host cells. Resistance to enfuvirtide is conferred by mutations occurring in the HR1 region involving residues 36-45. Mozambique, a sub-Saharan country, with an HIV prevalence of 11.5%, provides first line and second line antiretroviral therapy (ART)-based treatment. In poor resource settings such as Mozambique the lack of adequate infrastructures, the high costs of viral load tests, and the availability of salvage treatment have hindered the intended objective of monitoring HIV treatment, suggesting an important concern regarding the development of drug resistance. The general aim of this study was to evaluate naturally occurring polymorphisms and resistance-associated mutations in the gp41 region of HIV-1 isolates from Mozambique. The study included 78 patients naive to ARV treatment and 28 patients failing first line regimen recruited from Centro de Saúde Alto-Maé situated in Maputo. The gp41 gene from 103 patients was sequenced and resistance-associated mutations for enfuvirtide were screened. Subtype analysis revealed that 96% of the sequences were classified as subtype C, 2% as subtype G, 1% as subtype A1, and the other 1% as a mosaic form composed of A1/C. No enfuvirtide resistance-associated mutations in HR1 of gp41 were detected. The major polymorphisms in the HR1 were N42S, L54M, A67T, and V72I. This study suggests that this new class of antiviral drug may be effective as a salvage therapy in patients failing first line regimens in Mozambique. However, further phenotypic studies are required to determine the clinical relevance of the polymorphisms detected in this study.

Topics: Adolescent; Adult; Amino Acid Sequence; Anti-HIV Agents; Child; Child, Preschool; Cluster Analysis; Drug Resistance, Viral; Enfuvirtide; Female; Genotype; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Middle Aged; Molecular Sequence Data; Mozambique; Mutation, Missense; Peptide Fragments; Phylogeny; Polymorphism, Genetic; RNA, Viral; Sequence Alignment; Sequence Analysis, DNA; Treatment Failure; Young Adult

Although approved by the U.S. Food and Drug Administration, enfuvirtide is rarely used in combination antiretroviral therapies (cART) to treat HIV-1 infection, primarily because of its intense dosing schedule that requires twice-daily subcutaneous injection. Here, we describe the development of enfuvirtide-loaded, degradable poly(lactic-co-glycolic) acid microparticles that provide linear in vitro release of the drug over an 18-day period. This sustained-release formulation could make enfuvirtide more attractive for use in cART.

Topics: Cell-Derived Microparticles; Delayed-Action Preparations; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; In Vitro Techniques; Microscopy, Confocal; Microscopy, Electron, Scanning; Peptide Fragments

HIV-1 membranes contain gp120-gp41 trimers. Binding of gp120 to CD4 and a coreceptor (CCR5 or CXCR4) reduces the constraint on metastable gp41, enabling a series of conformational changes that cause membrane fusion. An analytic difficulty occurs because these steps occur slowly and asynchronously within cohorts of adsorbed virions. We previously isolated HIV-1JRCSF variants that efficiently use CCR5 mutants severely damaged in the tyrosine-sulfated amino terminus or extracellular loop 2. Surprisingly, both independent adaptations included gp120 mutations S298N, F313L, and N403S, supporting other evidence that they function by weakening gp120's grip on gp41 rather than by altering gp120 binding to specific CCR5 sites. Although several natural HIV-1 isolates reportedly use CCR5(Δ18) (CCR5 with a deletion of 18 N-terminal amino acids, including the tyrosine-sulfated region) when the soluble tyrosine-sulfated peptide is present, we show that HIV-1JRCSF with the adaptive mutations [HIV-1JRCSF(Ad)] functions approximately 100 times more efficiently and that coreceptor activation is reversible, enabling synchronous efficient entry control under physiological conditions. This system revealed that three-stranded gp41 folding intermediates susceptible to the inhibitor enfuvirtide form slowly and asynchronously on cell surface virions but resolve rapidly, with virions generally forming only one target. Adsorbed virions asynchronously and transiently become competent for entry at 37°C but are inactivated if the CCR5 peptide is absent during their window of opportunity. This competency is conferred by endocytosis, which results in inactivation if the peptide is absent. For both wild-type and adapted HIV-1 isolates, early gp41 refolding steps obligatorily occur on cell surfaces, whereas the final step(s) is endosomal. This system powerfully dissects HIV-1 entry and inhibitor mechanisms.. We present a powerful means to reversibly and efficiently activate or terminate HIV-1 entry by adding or removing a tyrosine-sulfated CCR5 peptide from the culture medium. This system uses stable cell clones and a variant of HIV-1JRCSF with three adaptive mutations. It enabled us to show that CCR5 coreceptor activation is rapidly reversible and to dissect aspects of entry that had previously been relatively intractable. Our analyses elucidate enfuvirtide (T-20) function and suggest that HIV-1 virions form only one nonredundant membrane fusion complex on cell surfaces. Additionally, we obtained novel and conclusive evidence that HIV-1 entry occurs in an assembly line manner, with some steps obligatorily occurring on cell surfaces and with final membrane fusion occurring in endosomes. Our results were confirmed for wild-type HIV-1. Thus, our paper provides major methodological and mechanistic insights about HIV-1 infection.

Topics: Amino Acid Sequence; CCR5 Receptor Antagonists; Cell Line; Endocytosis; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Peptide Fragments; Peptides; Receptors, CCR5; Sequence Alignment; Tyrosine; Virus Internalization

To develop new HIV-1 fusion inhibitors with improved antiviral activities and resistance profiles, we designed two categories of artificial peptides, each containing four heptad repeats (m4HR) conjugated with a pocket-specific small molecule (pssm) or pssm and cholesterol (chol), designated pssm-m4HR or pssm-m4HR-chol, respectively, and tested their anti-HIV-1 activity.. We synthesized the artificial peptides and conjugated these peptides with pssm and chol using a standard solid-phase Fmoc protocol and a chemoselective thioether conjugation method, respectively. We tested the inhibitory activities of the peptide conjugates against HIV-1 Env-mediated cell-cell fusion and infection by laboratory-adapted and primary HIV-1 isolates, and enfuvirtide-resistant HIV-1 strains using cell-cell fusion and p24 production assays, respectively. We assessed their cytotoxicity towards MT-2 cells using the XTT assay.. We found that pssm-m4HR conjugates exhibited promising inhibitory activity against HIV-1 Env-mediated cell-cell fusion and laboratory-adapted HIV-1 replication with IC50 values at the low micromolar level, whereas the pssm-m4HR-chol conjugates exhibited dramatically increased anti-HIV-1 activities with IC50 values at the low nanomolar level. Some of the pssm-m4HR-chol conjugates (e.g. 5a and 5b) showed highly potent antiviral activity against infection by primary HIV-1 isolates and enfuvirtide-resistant HIV-1 strains. All the conjugates displayed no or low cytotoxicity towards MT-2 cells. The result of a prime/wash assay indicated pssm-m4HR-chol conjugates were strongly anchored to the membrane and sustained a potent inhibitory effect after washing.. These results suggest this scaffold design is a promising strategy for developing novel peptide conjugates with improved antiviral activity against a broad spectrum of HIV-1 strains, including those highly resistant to enfuvirtide.

Topics: Amino Acid Sequence; Antiviral Agents; Cell Line; Cholesterol; Drug Design; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Membrane Fusion; Microbial Sensitivity Tests; Models, Molecular; Molecular Sequence Data; Peptide Fragments; Peptides; Protein Conformation

Previous studies demonstrate that soluble HIV proteins impact both hepatocyte function and HCV replication in vitro. It has also been reported that HIV can productively infect hepatocytes. We therefore investigated the impact of HIV infection of hepatocytes on HCV expression. The Huh7.5JFH1 cell line that constitutively expresses infectious HCV was infected with the lab-adapted strains HIVNL4-3 or HIVYK-JRCSF. HCV expression was quantified via HCV core antigen ELISA, Western blot, and strand-specific real-time PCR for positive-sense and negative-sense HCV RNA. After HIVNL4-3 infection of Huh7.5JFH1 cells, positive-sense and negative-sense HCV RNA levels were elevated compared to HIV uninfected cells. Increased HCV RNA synthesis was also observed after infection of Huh7.5JFH1 cells with HIVYK-JRCSF. HIV-induced HCV core production was decreased in the presence of the anti-HIV drugs AZT, T20, and raltegravir, although these medications had a minimal effect on HCV expression in the absence of HIV. HCV core, NS3, and NS5A protein expression were increased after HIV infection of Huh7.5JFH1 cells. Chemically inactivated HIV had a minimal effect on HCV expression in Huh7.5JFH1 cells suggesting that ongoing viral replication was critical. These data demonstrate that HIV induces HCV RNA synthesis and protein production in vitro and complement previous in vivo reports that HCV RNA levels are elevated in individuals with HIV/HCV co-infection compared to those with HCV mono-infection. These findings suggest that HIV suppression may be a critical factor in controlling liver disease, particularly if the underlying liver disease is not treated.

Topics: Cell Line; Enfuvirtide; Hepacivirus; Hepatocytes; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; Real-Time Polymerase Chain Reaction; Virus Replication; Zidovudine

HIV-1 gp41 is an envelope protein that plays an essential role in virus entry. The mutation of gp41 affects HIV-1 entry and susceptibility to the fusion inhibitor T-20. Therefore, we analyzed the natural polymorphism of gp41 of 163 HIV-1 isolates from T-20-naïve Koreans infected with HIV-1. This study of gp41 polymorphisms showed that insertions in the fourth threonine (74.8%) and L7M substitutions (85.3%) were more frequent in the fusion peptide motif in Korean HIV-1 isolates compared with those from other countries. Minor T-20 resistance mutations such as L45M (1.2%), N126K (1.2%), and E137K (6.7%) were detected, but the critical T-20 resistance mutations were not detected in the gp41 HR1 and HR2 regions. In addition, the N42S mutation (12.9%) associated with T-20 hypersusceptibility was detected at a high frequency. These results may serve as useful data for studies considering T-20 for use in the development of a more effective anti-retroviral treatment in Korea.

Topics: Anti-HIV Agents; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Peptide Fragments; Polymorphism, Genetic; Protein Structure, Tertiary; Republic of Korea; Virus Internalization

By a scaffold elongation strategy, a series of (Z)-3-(5-(3-benzyl-4-oxo-2-thioxothiazolidinylidene)methyl)-N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrroles and related derivatives with a linear multi-aromatic-ring skeleton were designed, synthesized, and evaluated in HIV-1 gp41 and cellular assays. Among them, the most active compounds, 12e, 12g, and 12k with a one-carbon linker (n=1) between the rhodanine (C) and phenyl (D) rings, exhibited very promising inhibitory potency with IC50 values of 1.8-2.6 μM and EC50 values of 0.3-1.5 μM against gp41 6-HB formation and HIV-1 replication in MT-2 cells, respectively. Additionally, they were almost equally effective against both T20-sensitive and resistant strains. The related SAR studies and molecular modeling results provided potential for further developing a new class of non-peptide small molecular fusion inhibitors targeting the HIV-1 gp41.

Topics: Anti-HIV Agents; Cell Line; Drug Design; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Molecular Docking Simulation; Pyrroles; Small Molecule Libraries

Enfuvirtide and T-1249 are two potent HIV-1 fusion inhibitor peptides. Recent studies indicate that lipids play an important role in the mode of action of those bioactive molecules. Using a combined tandem atomic force microscopy (AFM)-epifluorescence microscopy approach, we studied the interaction of both enfuvirtide and T-1249 with supported lipid bilayers. Fluid (ld)-gel (so) and ld-liquid ordered (lo) phase-separated membrane systems were tested. Results, especially for T-1249, show significant lipid membrane activity at a 15μM peptide concentration. T-1249, in opposition to enfuvirtide, induces an increase in membrane surface roughness, decrease in membrane fluidity, bilayer thinning at ld domains and disruption of the so domain borders. In terms of structural properties, both enfuvirtide and T-1249 possess distinct functional hydrophobic and amphipathic domains of HIV gp41. While enfuvirtide only yields the tryptophan-rich domain (TRD), T-1249 possesses both TRD and pocket-binding domain (PBD). TRD increases the hydrophobicity of the peptide while PBD enhances the amphipathic characteristics. As such, the enhanced membrane activity of T-1249 may be explained by a synergism between its amphipathic N-terminal segment and its hydrophophic C-terminal. Our findings provide valuable insights on the molecular-level mode of action of HIV-1 fusion inhibitors, unraveling the correlation between their structural properties and membrane interactions as a factor influencing their antiviral activity. Ultimately, this work validates the applicability of a combined AFM and fluorescence approach to evaluate the mechanic and structural properties of supported lipid bilayers upon interaction with membrane-active peptides.

Topics: Cell Membrane; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Lipid Bilayers; Membrane Fluidity; Membrane Lipids; Microscopy, Atomic Force; Microscopy, Fluorescence; Peptide Fragments

Mother-to-child transmission (MTCT) of HIV infection is now uncommon in the UK and the management of HIV-positive pregnant women is usually relatively straightforward. However, HIV viral load suppression may be difficult to achieve peripartum for women who book very late in pregnancy and those with a poor adherence to antiretroviral therapy (ART). These pregnancies are at a higher risk of MTCT due to high viral load (VL). Therefore, the development of interventions to achieve a rapid reduction of HIV VL is essential. We describe three relevant cases that presented to our unit over a 12-month period and discuss the strategies employed to manage these challenging cases. All babies were born healthy and were HIV proviral DNA-negative at 12 weeks postpartum. No serious adverse events were reported for the mothers or their babies.

Topics: Adult; Anti-Retroviral Agents; Directly Observed Therapy; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Hospitalization; Humans; Infectious Disease Transmission, Vertical; Peptide Fragments; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load

Peptides derived from the C-terminal heptad repeat (C peptides) of HIV-1 gp41 are potent inhibitors against virus entry. However, development of a short C peptide possessing high anti-HIV potency is considered a daunting challenge. We recently discovered that the residues Met626 and Thr627 preceding the pocket-binding domain of the C peptide adopt a unique M-T hook structure that is crucial for the design of HIV-1 fusion inhibitors. In this study, we first presented a proof-of-concept prototype that the M-T hook residues can dramatically improve the antiviral activity and thermostability of a short C peptide. We then generated a 24-mer peptide termed MT-SC22EK by incorporating the M-T hook structure to the N terminus of the poorly active short C peptide SC22EK. Amazingly, MT-SC22EK inhibited HIV-1-mediated cell fusion and infection at a level comparable to C34, T1249, SC29EK, and sifuvirtide, and it was highly active against diverse HIV-1 subtypes and variants, including those T20 (enfuvirtide) and SC29EK-resistant viruses. The high-resolution crystal structure of MT-SC22EK reveals the N-terminal M-T hook conformation folded by incorporated Met626 and Thr627 and identifies the C-terminal boundary critical for the anti-HIV activity. Collectively, our studies provide new insights into the mechanisms of HIV-1 fusion and its inhibition.

Topics: Cell Line; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Oligopeptides; Peptide Fragments; Peptides; Protein Structure, Secondary; Protein Structure, Tertiary

For the expression of late viral genes, HIV-1 efficiently exploits the nuclear export by using Rev viral protein, which specifically binds the RNA Rev Responsive Element (RRE). This region is contained within the gp120-gp41 encoding sequence. Enfuvirtide is the first approved HIV-1 fusion-inhibitor, and gp41 codons associated with primary enfuvirtide-resistance (amino-acids 36-45) are localized within the RRE structure. We previously found the co-presence of V38A+T18A resistance mutations in patients failing enfuvirtide.. Collecting 476 and 135 HIV-1 B-subtype gp41 sequences from enfuvirtide-naïve and enfuvirtide-treated patients, respectively, two mutations previously found associated with enfuvirtide treatment, T18A and V38A, were analyzed. Moreover, the RNA secondary structure was displayed by CONTRAfold-software and the gp41 evolutionary pathways by a mutagenetic tree.. By modeling the RRE structure, we show that the T18 and V38 codons are base pairing within the RRE-stem-IIA, an important domain involved in Rev binding. While a structural RRE impairment in the presence of V38A alone was found, a restoration of the original RRE structure occurred in co-presence of V38A+T18A. By mutagenetic tree analysis, a compensatory evolution confirming our hypothesis on the structural modification mechanism was observed.. We show that enfuvirtide pressure may also affect specific RRE domains involved in Rev binding, thus requiring a compensatory evolution able to preserve the secondary structure of the RRE.

Topics: Amino Acid Substitution; Anti-HIV Agents; Base Pairing; Drug Resistance, Viral; Enfuvirtide; Genes, env; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Models, Molecular; Mutation, Missense; Nucleic Acid Conformation; Peptide Fragments; RNA, Viral

The baseline susceptibility of primary HIV-2 to maraviroc (MVC) and other entry inhibitors is currently unknown.. The susceptibility of 19 HIV-2 isolates obtained from asymptomatic and AIDS patients and seven HIV-1 clinical isolates to the fusion inhibitors enfuvirtide (ENF) and T-1249, and to the coreceptor antagonists AMD3100, TAK-779 and MVC, was measured using a TZM-bl cell-based assay. The 50% inhibitory concentration (IC(50)), 90% inhibitory concentration (IC(90)) and dose-response curve slopes were determined for each drug.. ENF and T-1249 were significantly less active on HIV-2 than on HIV-1 (211- and 2-fold, respectively). AMD3100 and TAK-779 inhibited HIV-2 and HIV-1 CXCR4 tropic (X4) and CCR5 tropic (R5) variants with similar IC(50) and IC(90) values. MVC, however, inhibited the replication of R5 HIV-2 variants with significantly higher IC(90) values (42.7 versus 9.7 nM; P<0.0001) and lower slope values (0.7 versus 1.3; P<0.0001) than HIV-1. HIV-2 R5 variants derived from AIDS patients were significantly less sensitive to MVC than variants from asymptomatic patients, this being inversely correlated with the absolute number of CD4(+) T-cells.. T-1249 is a potent inhibitor of HIV-2 replication indicating that new fusion inhibitors might be useful to treat HIV-2 infection. Coreceptor antagonists TAK-779 and AMD3100 are also potent inhibitors of HIV-2 replication. The reduced sensitivity of R5 variants to MVC, especially in severely immunodeficient patients, indicates that the treatment of HIV-2-infected patients with MVC might require higher dosages than those used in HIV-1 patients, and should be adjusted to the disease stage.

Topics: Amides; Anti-HIV Agents; CCR5 Receptor Antagonists; Cyclohexanes; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; HIV-2; Humans; Inhibitory Concentration 50; Male; Maraviroc; Microbial Sensitivity Tests; Peptide Fragments; Quaternary Ammonium Compounds; Triazoles

Resistance to the fusion inhibitor enfuvirtide (ENF) is achieved by changes in the gp41 subunit of the HIV envelope glycoprotein (Env). Specific ENF-associated mutational pathways correlate with immunological recovery, even after virological failure, suggesting that the acquisition of ENF resistance alters gp41 pathogenicity. To test this hypothesis, we have characterized the expression, fusion capability, induction of CD4+ T cell loss and single CD4+ T cell death of 48 gp41 proteins derived from three patients displaying different amino acids (N, T or I) at position 140 that developed a V38A mutation after ENF-based treatment.. In all cases, intra-patient comparison of Env isolated pre- or post-treatment showed comparable values of expression and fusogenic capacity. Furthermore, Env with either N or T at position 140 induced comparable losses of CD4+ T-cells, irrespective of the residue present at position 38. Conversely, Env acquiring the V38A mutation in a 140I background induced a significantly reduced loss of CD4+ T cells and lower single-cell death than did their baseline controls. No altered ability to induce single-cell death was observed in the other clones.. Overall, primary gp41 proteins with both V38A and N140I changes showed a reduced ability to induce single cell death and deplete CD4+ T cells, despite maintaining fusion activity. The specificity of this phenotype highlights the relevance of the genetic context to the cytopathic capacity of Env and the role of ENF-resistance mutations in modulating viral pathogenicity in vivo, further supporting the hypothesis that gp41 is a critical mediator of HIV pathogenesis.

Topics: Amino Acid Sequence; Amino Acid Substitution; Anti-HIV Agents; CD4-Positive T-Lymphocytes; Cell Survival; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutant Proteins; Mutation, Missense; Peptide Fragments; Virulence; Virulence Factors

The present study describes a follow-up of a prospective and observational cohort of patients infected with HIV-1 and treated with raltegravir for salvage therapy in Brazil. Two groups of patients were analyzed: switching from T20 to RAL (Group 1, n = 9) and salvage therapy containing RAL (Group 2, n = 10). Blood samples were drawn for CD4(+) T-cell counts and HIV-1 viral load determinations. Protease, reverse transcriptase, and integrase genotyping were performed at baseline and at the time of virologic failure. CD4(+) T-cells increased at 6 and 12 months in both groups; HIV-1 viral load was continuously suppressed for Group 1, and for Group 2 it significantly decreased after starting a RAL-containing regimen. Three out of 10 patients from Group 2 could not suppress HIV-1 viral load. The mutations Q148H + G140S were observed for two patients and for the third patient only mutations to PR/RT inhibitors were detected. The genotypic sensitivity score (GSS) was analyzed for all patients of Group 2 and both patients who developed resistance to raltegravir presented a GSS < 2.0 for the RAL-containing scheme, which could be associated to the lack of effectiveness of the proposed scheme. The present study describes, for the first time in Brazil, the close follow-up of a series of patients using a raltegravir-containing HAART, showing the safety of the enfuvirtide switch to RAL and the effectiveness of a therapeutic regimen with RAL in promoting immune reconstitution and suppressing HIV replication, as well as documenting the occurrence of resistance to integrase inhibitors in the country.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Brazil; CD4 Lymphocyte Count; Cyclohexanes; Drug Resistance, Viral; Enfuvirtide; Follow-Up Studies; Genotyping Techniques; HIV Envelope Protein gp41; HIV Infections; HIV Integrase; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Maraviroc; Mutation; Peptide Fragments; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Salvage Therapy; Treatment Outcome; Triazoles; Viral Load; Virus Replication

Enfuvirtide belongs to a newer class of antiretroviral (ARV) agents called fusion inhibitors for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Enfuvirtide blocks attachment, binding, and entry of the viral capsid into the host CD4+ cell. Administration is only available subcutaneously in a twice-daily regimen particularly for those patients who have previously failed more than one ARV regimen. Common side effects of enfuvirtide administration include fatigue, insomnia, nausea, and diarrhea; however, injection-site reactions are the most common side effect and present in nearly all individuals undergoing treatment. The spectrum of cutaneous manifestations ranges from little to no reaction to cysts, nodules, induration, or sclerodermalike lesions. These reactions are mostly variants of iatrogenically induced hypersensitivity and are self-limited.

Topics: Cysts; Drug Eruptions; Enfuvirtide; Epidermal Cyst; Erythema; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Injections, Subcutaneous; Patient Selection; Peptide Fragments; Pruritus

It has been suggested that patients who initiate highly active antiretroviral therapy (HAART) late in their course of infection may have suboptimal CD4 T-cell gains, persistent alterations in T-cell subsets and residual inflammation. To address this issue, we carried out a comprehensive 48-week immunological study in HIV-infected patients who had experienced failures of prior therapies, had low CD4 cell counts, and were receiving enfuvirtide-based salvage therapy.. Immunological monitoring of peripheral lymphocytes from enfuvirtide-responder patients was performed over a 48-week period. A detailed assessment of immune cell subsets, their activation state [CD38 and human leucocyte antigen (HLA)-DR expression] and homeostasis [activation-induced cell death (AICD) and Ki67 expression], and the expression of co-receptors was performed by flow cytometry. Cytokine and chemokine signatures were assessed using multianalyte profiling technology.. Enfuvirtide-based salvage therapy induced a progressive restoration of naïve and central memory CD4 T cells, associated with a decrease in their activation state, suppression of premature priming for AICD and increased expression of Ki67. In addition, a significant decrease in C-C chemokine receptor 5 (CCR5) expression was detected on CD4 T cells, which was strongly correlated with the suppression of immune activation. Changes in circulating proinflammatory molecules occurred; i.e. there were decreases in the concentrations of interleukin (IL)-12, macrophage inflammatory protein MIP-1α, MIP-1β, monokine induced by IFNγ (MIG) and interferon-γ-inducible protein-10 (IP-10). The decline in circulating IL-12 and IP-10 was correlated with both the reduction in the viral load and CD4 T-cell restoration.. This study shows that suppression of HIV-1 replication with enfuvirtide-based salvage therapy in patients with low CD4 cell counts may result in an immunological benefit, characterized by the restoration of CD4 T-cell subsets associated with decreased immune activation and suppression of inflammation.

Topics: Adolescent; Adult; Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; Chemokine CXCL10; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Interleukin-12; Longitudinal Studies; Male; Middle Aged; Peptide Fragments; Receptors, CCR5; Salvage Therapy; Viral Load; Virus Replication; Young Adult

Recently, the first drug in a new class of antiretroviral HIV drugs was approved, the fusion inhibitor enfuvirtide. We develop a mathematical model that describes the binding of the virus to T cells. We model the effect of enfuvirtide upon this process using impulsive differential equations. We find equilibria and determine stability in the case of no therapy and then when therapy is taken with perfect adherence. We determine analytical thresholds for the dosage and dosing intervals to ensure the disease-free equilibrium remains stable. We also explore the effects of partial adherence. Our theoretical results suggest that partial adherence may, at times, be worse than no therapy at all, but at other times may in fact as good as perfect adherence. It follows that patients should be counselled on the importance of adherence to this new antiretroviral drug.

Topics: Algorithms; CD4-Positive T-Lymphocytes; Dose-Response Relationship, Drug; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Models, Biological; Peptide Fragments; Time Factors

Evaluation of the dynamics of enfuvirtide (ENF) resistance mutations after ENF withdrawal in patients with virological failure under salvage therapy may be helpful to optimize the management of ENF in human immunodeficiency virus (HIV)-infected patients.. Seven patients with a failing ENF-containing regimen, initiated for at least 3 months (median 6.4 months, range 3-14), were included and followed up prospectively at the time of virological failure. Genotypic analysis of the gp41 region by bulk sequencing and clonal analysis was performed in plasma and/or peripheral blood mononuclear cells to detect ENF resistance mutations.. Genotypic profiles of ENF-resistant variants at ENF discontinuation were as follows: V38A in 3 patients, V38A+N42T+N43D in 1 patient, N43D in 2 patients, and N43K in 1 patient. Clonal analysis showed that maintaining ENF treatment after virological failure has an impact on both (1) the number of resistance profiles detected, and (2) the time of persistence of ENF-resistant variants. ENF-resistant variants were archived in HIV DNA in 5/7 patients. At 1 month after ENF withdrawal, no significant increase in HIV-1 viral load was observed.. The persistence of ENF-resistant variants was found to be correlated to exposure time to failing drug. ENF withdrawal should be considered in patients with virological failure to preserve the possible efficacy of ENF recycling or upcoming entry inhibitors.

Topics: Adult; CD4 Lymphocyte Count; Drug Resistance, Viral; Enfuvirtide; Evolution, Molecular; Female; Follow-Up Studies; Genotype; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Mutation; Peptide Fragments; Prospective Studies; RNA, Viral; Salvage Therapy; Treatment Failure; Viral Load

The data on the use of tipranavir and enfuvirtide in pregnancy are very limited. We performed a pharmacokinetic profile in a pregnant woman with multidrug-resistant HIV-1 infection at 37 weeks gestation. Tipranavir levels were in the therapeutic range and the cord blood concentration at delivery was relatively high when compared with other protease inhibitors. No enfuvirtide was detected in the fetal compartment. Tipranavir and enfuvirtide were successfully used in pregnancy, but possible toxicities must be kept in mind.

Topics: Adult; Anti-HIV Agents; Enfuvirtide; Female; Fetal Blood; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Plasma; Pregnancy; Pregnancy Complications, Infectious; Pyridines; Pyrones; Sulfonamides

We compared tipranavir and darunavir concentrations measured at steady state in 20 human immunodeficiency virus (HIV)-infected patients enrolled in the EASIER-ANRS 138 clinical trial who switched from enfuvirtide to raltegravir while maintaining the same background regimen. The geometric mean ratios of the observed predose concentration (C(trough)), maximum concentration of drug observed in plasma (C(max)), and area under the plasma concentration-time curve (AUC) before (day 0) and after (week 24) the switch were 0.49, 0.76, and 0.67 and 0.82, 0.68, and 0.64 for tipranavir and darunavir, respectively. The virologic consequences of these drug interactions have yet to be determined.

Topics: Anti-HIV Agents; Darunavir; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; Humans; Male; Middle Aged; Peptide Fragments; Pyridines; Pyrones; Ritonavir; Sulfonamides

Topics: Darunavir; Drug Resistance, Viral; Enfuvirtide; Genotype; HIV; HIV Envelope Protein gp41; HIV Infections; HIV Protease Inhibitors; Humans; Logistic Models; Peptide Fragments; Point Mutation; Sulfonamides

To evaluate the polymorphisms and resistance mutations in gp41 HR1 region of HIV-1.. The study included 28 HIV-positive patients undergoing enfuvirtide (ENF) treatment or not from Porto Alegre, Rio Grande do Sul state, and Rio de Janeiro, Rio de Janeiro state, between 2006 and 2009. Resistance mutations and polymorphisms of the gp41 HR1 region were detected using the genomic DNA of 12 ENF-untreated patients and 16 patients in ENF treatment, encompassing subtypes B, C, and F1. Sample subtypes were determined by neighbor-joining phylogenetic analysis with a Kimura's two-parameter correction.. A high prevalence of polymorphisms unrelated to resistance was observed. Among ENF-untreated patients, 16% showed mutations related with resistance. Among patients in ENF treatment, 50% had resistance-related mutations. Overall, 17% of all isolates showed the N42S polymorphism related to ENF hypersusceptibility. The presence of ENF resistance mutations in the group of treated patients reduced viral load. The V38A substitution was the most frequent among treatment-experienced patients followed by the G36D/E, N42D, and V38M substitutions.. The V38A substitution in the gp41 HR region was the most common resistance mutation among ENF-treated patients and was associated with increased viral load.

Topics: Amino Acid Substitution; Anti-HIV Agents; Cluster Analysis; Drug Resistance, Viral; Enfuvirtide; Genotype; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation, Missense; Peptide Fragments; Phylogeny; Polymorphism, Genetic; Sequence Analysis, DNA

Enfuvirtide (T-20), a C-terminal heptad repeat (C-HR)-derived peptide of HIV-1 glycoprotein, gp41, effectively suppresses HIV-1 replication through a putative mechanism that involves it acting as a decoy and binding to the N-terminal heptad repeat (N-HR) of the virus. In this study, we address whether the anti-HIV-1 activity of T-20 is antagonized by a variety of N-HR-derived peptides.. Multinuclear activation of galactosidase indicator assays were used to evaluate T-20 activity in the presence of N-HR-derived peptides. The gp41-derived peptides were chemically synthesized.. We demonstrate additive anti-HIV activity when T-20 is used in combination with N-HR-derived peptides that do not have a putative binding region for the tryptophan-rich domain in T-20. The presence of a deep pocket-forming region in the N-HR-derived peptides enhanced their anti-HIV-1 activity, but had little effect on the activity of T-20.. These results indicate that T-20-based antiviral therapies can be combined with N-HR-derived peptides.

Topics: Amino Acid Sequence; Anti-HIV Agents; Binding Sites; Cell Line; Drug Synergism; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Peptide Fragments; Peptides

T-20 (also known as enfuvirtide) is a fusion inhibitor peptide known to have some effectiveness in the control of progression of HIV infection by inhibiting the fusion of the HIV envelope with the target cell membrane. Recent results indicate that T-20 is able to interact with membranes in the liquid disordered state but not with membranes in an ordered state, which could be linked to its effectiveness. A detailed molecular picture of the interaction of these molecules with membranes is still lacking. To this effect, extensive molecular dynamics simulations (100 ns) were carried out to investigate the interaction between T-20 and bilayers of 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and POPC/cholesterol (1:1). Membrane properties such as area/lipid, density profiles, order parameters and membrane thickness were studied. It was observed that T-20 has the ability to interact to different extents with both model membranes in this study and that peptide interaction with the bilayer surface has a local effect on membrane structure. The formation of hydrogen bonding between certain peptide residues and the POPC phosphate group was observed. However, T-20 showed a more limited extent of interaction with model membranes when compared with other, more efficient, peptides (such as T-1249). This effect is most notable in POPC/Chol membranes in which interaction is especially weak, owing to less peptide residues acting as H bond donors to POPC and virtually no H bonds being formed between T-20 and cholesterol. This lower ability to interact with membranes is probably correlated with its smaller inhibitory efficiency.

Topics: Cholesterol; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Lipid Bilayers; Molecular Dynamics Simulation; Peptide Fragments; Phosphatidylcholines

Vaginally applied microbicides hold promise as a strategy to prevent sexual HIV transmission. Several nonspecific microbicides, including the polyanion cellulose sulfate, have been evaluated in large-scale clinical trials but have failed to show significant efficacy. These findings have prompted a renewed search for preclinical testing systems that can predict negative outcomes of microbicide trials. Moreover, the pipeline of potential topical microbicides has been expanded to include antiretroviral agents, such as reverse transcriptase, fusion, and integrase inhibitors. Using a novel ex vivo model of vaginal HIV-1 infection, we compared the prophylactic potentials of two forms of the fusion inhibitor T-20, the CCR5 antagonist TAK-778, the integrase inhibitor 118-D-24, and cellulose sulfate (Ushercell). The T-20 peptide with free N- and C-terminal amino acids was the most efficacious compound, causing significantly greater inhibition of viral genomic integration in intraepithelial vaginal leukocytes, measured by an optimized real-time PCR assay, than the more water-soluble N-acetylated T-20 peptide (Fuzeon) (50% inhibitory concentration [IC50], 0.153 microM versus 51.2 microM [0.687 ng/ml versus 230 ng/ml]; P<0.0001). In contrast, no significant difference in IC50s was noted in peripheral blood cells (IC50, 13.58 microM versus 7.57 microM [61 ng/ml versus 34 ng/ml]; P=0.0614). Cellulose sulfate was the least effective of all the compounds tested (IC50, 1.8 microg/ml). These results highlight the merit of our model for screening the mucosal efficacies of novel microbicides and their formulations and potentially rank ordering candidates for clinical evaluation.

Topics: Adult; Anti-HIV Agents; Benzothiepins; Cells, Cultured; Enfuvirtide; Female; Flow Cytometry; Genotype; HIV Envelope Protein gp41; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; In Vitro Techniques; Microscopy, Confocal; Peptide Fragments; Polymerase Chain Reaction; Virus Integration

We assessed the natural genotypic and phenotypic susceptibilities to enfuvirtide of 171 HIV group O (HIV-O) samples and 29 strains, respectively. The N42D resistance-associated mutation in the gp41 region was detected in 98% of cases. The phenotypic assay showed a wide range of baseline susceptibilities, with 50% inhibitory concentrations (IC(50)s) from 4 to 5,000 nM, a range similar to that reported for HIV-1 group M. Thus, despite the natural genotypic resistance conferred by the N42D signature mutation, HIV-O variants appear to be phenotypically susceptible. Enfuvirtide could therefore potentially be used in antiretroviral treatments for HIV-O-infected patients.

Topics: Anti-HIV Agents; Enfuvirtide; Genotype; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Inhibitory Concentration 50; Molecular Sequence Data; Peptide Fragments; Phenotype

Pooled analysis of the TORO comparative clinical trial data sets showed a significantly higher incidence rate (IR) of bacterial pneumonia (BP) among patients treated with enfuvirtide-containing combination antiretroviral therapy (ENF-cART) than in those treated with other cART regimens.. To examine the possible impact of ENF-cART on the risk of BP.. From the French Hospital Database on HIV, we selected two groups of patients among cART-treated patients who were prescribed a new cART regimen during the period 2001-2006, when their CD4 counts were <350 cells/mm(3). The ENF-cART and cART groups consisted of 1220 and 9374 patients, respectively. Poisson regression models were used to quantify the relationship between ENF-cART therapy and the risk of BP.. At baseline the median CD4 counts were 100 and 211 cells/mm(3) and the median plasma viral load (pVL) values were 60 276 and 2702 copies/mL in the ENF-cART and cART groups, respectively. The respective BP IRs were 0.65 [95% confidence interval (CI) 0.25-1.06] and 0.31 (95% CI 0.25-0.38) cases per 100 person-years. After adjustment for age, the HIV transmission group, the time period, co-trimoxazole prophylaxis, and stratified CD4 cell counts and pVL values, we found that the BP risk ratio was not increased by enfuvirtide treatment (relative rate 1.39; 95% CI 0.46-4.13). In contrast, lower CD4 cell counts and higher pVL values were significantly associated with a higher risk of BP.. ENF-cART is not associated with a significantly higher risk of BP than other cART regimens, although the value of the adjusted risk and the upper limit of the CI do not allow us to exclude a small increased risk.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Enfuvirtide; Female; France; HIV Envelope Protein gp41; HIV Infections; Humans; Incidence; Male; Middle Aged; Peptide Fragments; Pneumonia, Bacterial; Risk Factors

We report the selection of enfuvirtide-resistant human immunodeficiency virus type 1 in cerebrospinal fluid, resulting in subsequent loss of viral suppression in the plasma. This case report emphasizes the potential danger of low-level penetration of entry inhibitors into the central nervous system.

Topics: Anti-HIV Agents; Cerebrospinal Fluid; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Selection, Genetic; Treatment Failure

We report an extreme case of high-grade needlestick exposure of a health-care worker to serum from multiple HIV-infected patients after trying to prematurely remove the respective tubes from an automated biochemical analyser. After review of the medical records of the eight source patients, we offered the health-care worker an expanded postexposure prophylaxis regimen including the entry inhibitor enfuvirtide. She refused to take subcutaneous injections, so we recommended the use of the integrase inhibitor raltegravir. She completed therapy without problems and periodic evaluation for HIV transmission up to nine months after the incident was negative.

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Darunavir; Deoxycytidine; Emtricitabine; Enfuvirtide; Female; Fingers; HIV Envelope Protein gp41; HIV Infections; Humans; Infectious Disease Transmission, Patient-to-Professional; Middle Aged; Needlestick Injuries; Occupational Diseases; Organophosphonates; Peptide Fragments; Post-Exposure Prophylaxis; Ritonavir; Sulfonamides; Tenofovir

Enfuvirtide (ENF) is a viral fusion inhibitor used in patients failing highly active antiretroviral therapy (HAART). Mutations associated with ENF resistance have been identified within amino acid positions 36-45 of gp41. As ENF will be introduced to Hong Kong, an understanding of the prevalence of naturally occurred ENF resistance mutations is important before implementation of ENF treatment.. To investigate the prevalence of ENF resistance-associated mutations in the HR1 and HR2 of HIV-1 strains obtained from ENF-naïve patients.. HIV-1 strains isolated from 185 patients (156 antiretroviral treatment [ART]-naïve and 29 HAART-experienced) were screened for ENF resistance-associated mutations using RT-PCR and DNA sequencing.. Primary mutations were detected in 19.4% of HARRT-experienced patients and 20.5% of ART-naïve patients. G36D was encountered most frequently and more prevalent in non-B subtypes. N42S, L54M and V69I were the major polymorphisms detected. N42S and L54M were predominant in CRF01_AE and subtype B, respectively. V69I was found in all samples harboring G36D. In three longitudinal samples from an ENF-treated patient, G36D was detected after ENF treatment for 6 months and the mutation persisted after termination of ENF for 6 months.. The high prevalence of ENF resistance-associated mutations in HARRT-experienced and ART-naïve patients identified in this study highlights the importance of mutation screening before ENF therapy in Hong Kong. Our findings from the ENF-treated patient showed that G36D mutation persisted as long as 6 months after ENF withdrawal. Phenotypic assays will be necessary to confirm the influence of this mutation to ENF susceptibility.

Topics: Anti-HIV Agents; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Hong Kong; Humans; Mutation, Missense; Peptide Fragments; Prevalence; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Sequence Analysis, DNA

Mutations that are selected at low frequency and/or reside outside the enfuvirtide target region, amino acid 36-45 of gp41, might still be important determinants for drug resistance. This study aimed to investigate the phenotypic impact against enfuvirtide and sifuvirtide of uncharacterized gp41 mutations 42G, 43T and 50V, selected in patients failing enfuvirtide-containing regimens. As single mutations, neither 42G, 43T nor 50V conferred resistance to enfuvirtide. However, 50V increased slightly resistance levels for 36D, 38M, 43D or 43T as did 43T for 38M. All mutants displayed a reduced replication capacity, except 42S, 50V and 36D+/-50V. None of the mutants displayed resistance to the next-generation fusion inhibitor sifuvirtide. This study highlights the necessity to confirm the in vitro effect of infrequently selected mutations as 42G was not associated with enfuvirtide resistance whereas 43T and 50V should be considered as secondary enfuvirtide resistance mutations.

Topics: Amino Acid Sequence; Anti-HIV Agents; Cell Line; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation, Missense; Peptide Fragments; Peptides; Virus Replication

The effect of enfuvirtide (ENF) in 11 HIV-1 heavily antiretroviral-experienced children and adolescents enrolled in the HIV-1 Paediatric Spanish cohort was further investigated. Patients who received ENF with novel drugs (etravirine, darunavir, and/or tipranavir) reached and maintained undetectable plasma HIV-1 RNA levels and showed immunological recovery within the first 3 months of therapy that was maintained during the follow-up. Viremia was not fully suppressed in patients who did not combine ENF with novel drugs but interestingly, immunological benefit was observed in half of these patients. Therefore, ENF showed a greater and more stable efficacy when administrated with novel drugs.

Topics: Adolescent; Child; Darunavir; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infectious Disease Transmission, Vertical; Nitriles; Peptide Fragments; Pyridazines; Pyridines; Pyrimidines; Pyrones; Sulfonamides; Time Factors; Treatment Outcome; Young Adult

We analyzed the gp41 sequences of 80 HIV-infected enfuvirtide-naive individuals who were eligible to receive this antiretroviral according to Brazilian guidelines. We analyzed the genetic diversity of pol and the heptad repeat 1 and 2 (HR1 and HR2) regions of gp41, and compared the genetic profile of HR1 and HR2 found in PBMCs with the profile found in plasma. The similarity between sequences obtained from DNA and RNA in the HR1 and HR2 regions was, on average, 98.6% and 98.9%, respectively. We detected mutations related to enfuvirtide resistance (L44M or N43K) in HR1 DNA samples from three individuals (3.8%) and RNA samples from three individuals (4.6%). Other polymorphisms frequently detected were E137K (10% and 13.8%), L130I (8.8% and 9.2%), S129N (6.3% and 10.8%), L44M (2.5% and 4.6%), S138A (2.5% and 1.5%), and N43K (1.3% and 0%) in DNA and RNA, respectively. Subtype B was identified in 68.8% of the samples [protease (PR) B, reverse transcriptase (RT) B, gp41 B], subtype F in 5.0%, subtype C in 1.3%, and the remaining sequences presented with a mosaic profile. These results suggest that genotyping the gp41 region prior to introducing an expensive and complex approach, such as enfuvirtide, may be cost effective. Moreover, assessment of proviral DNA may be less expensive than RNA, as well as being sufficient for this purpose.

Topics: Adult; Brazil; DNA, Viral; Drug Resistance, Viral; Enfuvirtide; Genetic Variation; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Middle Aged; Peptide Fragments; pol Gene Products, Human Immunodeficiency Virus; Polymorphism, Single Nucleotide; RNA, Viral; Treatment Outcome

The randomized, placebo-controlled Phase III DUET studies enrolled treatment-experienced, HIV-1-infected patients. We examined the genotypic and phenotypic changes at endpoint relative to baseline, including the emergence of individual reverse transcriptase (RT) mutations, in patients who received the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine and experienced virologic failure by rebound by the time of the Week 96 analysis. Patients received etravirine 200 mg twice-daily in combination with a background regimen containing darunavir/ritonavir, investigator-selected nucleoside reverse transcriptase inhibitors, and optional enfuvirtide. Virologic failure by rebound occurred in 93 (15.5%) etravirine-treated patients (compared with 170 [28.1%] placebo-treated patients). Patients experiencing virologic failure had more baseline antiretroviral resistance and lower activity of the background regimen relative to those not experiencing failure. Emergence of NNRTI resistance-associated mutations was observed in 55 of 93 patients. The most frequently emerging RT mutations were V179F, V179I, and Y181C, with positions K101 and E138 also showing frequent changes. Mutations usually emerged in a background of multiple other NNRTI mutations and were, in most cases, associated with a decrease in phenotypic sensitivity to etravirine at endpoint. Further analysis is needed to clarify the role of mutations at position 138 as determinants of etravirine resistance.

Topics: Amino Acid Substitution; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Clinical Trials, Phase III as Topic; Darunavir; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Microbial Sensitivity Tests; Mutation, Missense; Nitriles; Peptide Fragments; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Ritonavir; Sequence Analysis, DNA; Sulfonamides; Treatment Failure; Viral Load

Enfuvirtide is a large protein that should be injected subcutaneously to ensure an appropriate absorption. Here we report the case of a transgender HIV-positive patient receiving enfuvirtide with an individualized background regimen of antiretroviral drugs, who had previously undergone liquid silicone oil injections. We performed US scan to detect silicone-free areas for following enfuvirtide injections. US can be useful in the correct management of those patients with liquid silicone oil soft tissue augmentation who require subcutaneously injected drugs.

Topics: Adult; Anti-HIV Agents; Breast Implants; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Male; Peptide Fragments; Silicone Oils; Subcutaneous Tissue; Transsexualism; Ultrasonography

Entry inhibitor is a new class of drugs that target the viral envelope protein. This region is variable; hence resistance to these drugs may be present before treatment. The aim of this study was to analyze the frequency of patients failing treatment with transcriptase reverse and protease inhibitors that would respond to the entry inhibitors Enfuvirtide, Maraviroc, and BMS-806. The study included 100 HIV-1 positive patients from one outpatient clinic in the city of Sao Paulo, for whom a genotype test was requested due to treatment failure. Proviral DNA was amplified and sequenced for regions of gp120 and gp41. A total of 80 could be sequenced and from those, 73 (91.3%), 5 (6.3%) and 2 (2.5%) were classified as subtype B, F, and recombinants (B/ F and B/C), respectively. CXCR4 co-receptor use was predicted in 30% of the strains. Primary resistance to Enfuvirtide was found in 1.3%, following the AIDS Society consensus list, and 10% would be considered resistant if a broader criterion was used. Resistance to BMS-806 was higher; 6 (7.5%), and was associated to non-B strains. Strikingly, 27.5% of samples harbored one or more mutation among A316T, I323V, and S405A, which have been related to decreased susceptibility of Maraviroc; 15% of them among viruses predictive to be R5. A more common mutation was A316T, which was associated to the Brazilian B strain harboring the GWGR motif at the tip of V3 loop and their derivative sequences. These results may be impact guidelines for genotype testing and treatment in Brazil.

Topics: Adult; Ambulatory Care Facilities; Anti-HIV Agents; Brazil; Cyclohexanes; DNA, Viral; Drug Resistance, Viral; Enfuvirtide; env Gene Products, Human Immunodeficiency Virus; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Male; Maraviroc; Middle Aged; Molecular Sequence Data; Mutation, Missense; Peptide Fragments; Piperazines; Prevalence; Proviruses; Sequence Analysis, DNA; Treatment Failure; Triazoles

To report a potential drug-drug interaction between enfuvirtide, an injectable HIV fusion inhibitor, and niacin in an HIV-infected man with dilated cardiomyopathy.. A 47-year-old HIV-infected man with dilated cardiomyopathy and prolonged QT syndrome with an automatic implantable cardiovascular defibrillator device was prescribed subcutaneous enfuvirtide 90 mg twice daily as part of his antiretroviral regimen and oral extended-release niacin 500 mg/day for a high-density lipoprotein level of 8 mg/dL. After 1 week of concomitant therapy, the patient began experiencing extreme redness, edema, and swelling at the injection site that corresponded with the flushing sensation due to niacin. This interfered with his daily activities, leading to self-discontinuation of both agents. As the patient had tolerated enfuvirtide therapy prior to the addition of niacin, we reinitiated enfuvirtide with close follow-up, and the patient has been maintained on this agent since then without consequence. Based on the Horn Drug Interaction Probability Scale, a probable interaction occurred between enfurvirtide and niacin.. We hypothesize that a drug-drug interaction occurs between enfuvirtide and niacin related to prostaglandin synthesis and mobilization of inflammatory cells, specifically Langerhans cells. A theoretical mechanism for this interaction is that the Langerhans cells in the epidermis function improperly due to the presence of HIV and the attachment of enfuvirtide. When these cells are exposed to nicotinic acid, an exaggerated immune response is produced that may lead to pain, redness, and swelling at the injection site. Prostaglandins, cytokines, and other inflammatory molecules may all have a role in this interaction.. Caution should be used when coadministering enfuvirtide and niacin to HIV-infected patients.

Topics: Delayed-Action Preparations; Drug Interactions; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Hypolipidemic Agents; Injections, Subcutaneous; Male; Middle Aged; Niacin; Peptide Fragments

Measuring drug resistance is one of the challenging and essential pharmaceutical activities. It is a laborious and costly laboratory-based experimentation. Various clinical and experimental analyses for measuring drug resistance have been carried out. Results have been obtained for different types of therapeutic agents as a consequence of changes in the amino acids compositions in the sequence (mutation) of the organisms involved. In the same manner, the positions of these amino acids alterations and the level of resistance (folds) have also been experimentally identified. For example, G36S and V38M mutation in the Human Immunodeficiency Virus (HIV) Transmembrane glycoprotein (gp41) has been found to cause 100-fold resistance. However, there does not seem to have bioinformatics method developed in which the amino acid information of the proteins involved in the studies were used to computationally assess the degree of drug resistance without involving laboratory-based experimental procedure. The post-genomic era has witnessed the relevance of Bioinformatics approaches in the analysis of huge biomedical data. One such approach is the analysis of protein residues using digital signal processing technique such as informational spectrum method (ISM). Therefore, we propose a new bioinformatics method that is capable of assessing drug resistance without the use of any laboratory-based experiments. This new method incorporates ISM, sequence information of the proteins and other relevant information. By using the ISM and EIIP amino acid scale, the technique was applied in three classes of anti-HIV/AIDS drugs as a case study. It is observed that the protein residues of the susceptible strains attained the maximal peak amplitude at the consensus frequency while the resistant strains maintained lower amplitudes. This result signifies lower contribution from the resistant strains due to the mutation. The findings are consistent with those of the experimental ones and therefore suggest that the approach taken can be used to help assess drug resistance without laboratory-based experimentation. It should also be noted that the method can be applied in other drug resistance studies where sequence information of proteins is available and help design a computer-aided drug resistance calculator.

Topics: Amino Acid Sequence; Anti-HIV Agents; Computational Biology; Drug Resistance; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Infections; Humans; Lamivudine; Molecular Sequence Data; Mutation; Peptide Fragments; Phenylpropionates; Pyrimidines; Signal Processing, Computer-Assisted

For most HIV-infected patients, antiretroviral therapy controls viral replication. However, in some patients drug resistance can cause therapy to fail. Nonetheless, continued therapy with a failing regimen can preserve or even lead to increases in CD4+ T cell counts. To understand the biological basis of these observations, we used mathematical models to explain observations made in patients with drug-resistant HIV treated with enfuvirtide (ENF/T-20), an HIV-1 fusion inhibitor. Due to resistance emergence, ENF was removed from the drug regimen, drug-sensitive virus regrown, and ENF was re-administered. We used our model to study the dynamics of plasma-viral RNA and CD4+ T cell levels, and the competition between drug-sensitive and resistant viruses during therapy interruption and re-administration. Focusing on resistant viruses carrying the V38A mutation in gp41, we found ENF-resistant virus to be 17±3% less fit than ENF-sensitive virus in the absence of the drug, and that the loss of resistant virus during therapy interruption was primarily due to this fitness cost. Using viral dynamic parameters estimated from these patients, we show that although re-administration of ENF cannot suppress viral load, it can, in the presence of resistant virus, increase CD4+ T cell counts, which should yield clinical benefits. This study provides a framework to investigate HIV and T cell dynamics in patients who develop drug resistance to other antiretroviral agents and may help to develop more effective strategies for treatment.

Topics: CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Models, Biological; Peptide Fragments; Prognosis; Treatment Outcome; Viral Load

We recently reported a beta(3)-decapeptide, betaWWI-1, that binds a validated gp41 model in vitro and inhibits gp41-mediated fusion in cell culture. Here we report six analogs of betaWWI-1 containing a variety of non-natural side chains in place of the central tryptophan of the WWI-epitope. These analogs were compared on the basis of both gp41 affinity in vitro and fusion inibition in live, HIV-infected cells. One new beta(3)-peptide, betaWXI-a, offers a significantly improved CC(50)/EC(50) ratio in the live cell assay.

Topics: Cell Line; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptides; T-Lymphocytes

Enfuvirtide (T-20) is a fusion inhibitor that suppresses replication of human immunodeficiency virus (HIV) variants with multi-drug resistance to reverse transcriptase and protease inhibitors. It is a peptide derived from the C-terminal heptad repeat (C-HR) of HIV-1 gp41, and it prevents interactions between the C-HR and the N-terminal HR (N-HR) of gp41, thus interfering with conformational changes that are required for viral fusion. However, prolonged therapies with T-20 result in the emergence of T-20-resistant strains that contain primary mutations such as N43D in the N-HR of gp41 (where T-20 and C-HR bind) that help the virus escape at a fitness cost. Such variants often go on to acquire a secondary mutation, S138A, in the C-HR of gp41 region that corresponds to the sequence of T-20. We demonstrate here that the role of S138A is to compensate for the impaired fusion kinetics of HIV-1s carrying primary mutations that abrogate binding of T-20. To preempt this escape strategy, we designed a modified T-20 variant containing the S138A substitution and showed that it is a potent inhibitor of both T-20-sensitive and T-20-resistant viruses. Circular dichroism analysis revealed that the S138A provided increased stability of the 6-helix bundle. We validated our approach on another fusion inhibitor, C34. In this case, we designed a variant of C34 with the secondary escape mutation N126K and showed that it can effectively inhibit replication of C34-resistant HIV-1. These results prove that it is possible to design improved peptide-based fusion inhibitors that are efficient against a major mechanism of drug resistance.

Topics: Amino Acid Substitution; Drug Design; Drug Resistance, Multiple; Drug Resistance, Viral; Enfuvirtide; HeLa Cells; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Mutation, Missense; Peptide Fragments; Virus Replication

Human immunodeficiency virus type 1 (HIV-1) env genes were cloned from blood samples of HIV-1-infected Thai patients, and 35 infectious CRF01_AE envelope glycoprotein (Env)-recombinant viruses were established. In this report, we examined the neutralization susceptibility of these viruses to human monoclonal antibodies, 2G12, IgG1 b12, 2F5 and 4E10, pooled patient plasma, coreceptor antagonists and fusion inhibitor, T-20. The neutralization susceptibility of CRF01_AE Env-recombinant viruses to 2F5, 4E10, patient plasma, coreceptor antagonists and T-20 varied, while most viruses showed low susceptibility to 2G12 and IgG1 b12. Several dual-tropic viruses showed lower susceptibility to 2F5 and 4E10 than CXCR4- or CCR5-tropic viruses. Neutralization susceptibility of the CRF01_AE Env-recombinant virus to pooled patient plasma was negatively correlated with the length of the V1/V2 region or the number of potential N-linked glycosylation sites in conserved regions of gp120. No correlation was found between the coreceptor usage and neutralization susceptibility of the virus to T-20, whereas several dual-tropic viruses showed higher susceptibility to coreceptor antagonists than CXCR4- or CCR5-tropic viruses. We propose that these CRF01_AE Env-recombinant viruses are useful to further study the molecular mechanism of the susceptibility of CRF01_AE Env to neutralizing antibodies and viral entry inhibitors.

Topics: Antibodies, Monoclonal; Enfuvirtide; env Gene Products, Human Immunodeficiency Virus; HIV Antibodies; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Neutralization Tests; Peptide Fragments; Receptors, HIV; Recombination, Genetic; Thailand

Fusion inhibitors can be an effective salvage therapy in HIV-patients with multiple resistances. However, the management and maintenance of the therapy, which requires percutaneous self-administration, can be a difficult task for patients. Preparation and administration are time-consuming and may force patients to alter their daily routine. Therefore, appropriate counselling and training is important. Evidence-based guidelines can help health care professionals to provide continuing high quality care. The department of Clinical Nursing Science at the University Hospital Basel have developed a nursing guideline, which formulates patient-management from decision-making up to the support needed in long-time treatment maintenance. The main focus of this article lies on the theoretical framework of this guideline and a description of its key elements. These are important aspects of managing the treatment of chronic illness in general. Therefore, this article addresses all health care providers supporting chronically ill patients in their medication management.

Topics: Enfuvirtide; Evidence-Based Medicine; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections, Subcutaneous; Models, Nursing; Patient Education as Topic; Peptide Fragments; Switzerland

Enfuvirtide is active against isolates from different HIV-1 subtypes. In vitro and in vivo studies reveal that resistance mutations are primarily found within the region spanning amino acid 36-45 of gp41. However, most studies include only subtype B strains, while it is known that especially the env region is very divergent among subtypes.. To analyze the gp41 HR1 genetic evolution during failure of enfuvirtide-containing salvage regimens in 19 HIV-1 patients infected with strains from different group M subtypes.. The gp41 sequence was determined at baseline and upon failure in 19 patients. For a subset of 7 patients, samples were available after discontinuation of enfuvirtide.. Our results confirmed the conserved nature of the HR1 region. Escape mutants during chronic treatment with enfuvirtide were mainly observed within region 36-45. One novel mutation was identified, i.e. S42G in a subtype A1 strain.. Different subtypes escape enfuvirtide selective pressure through similar mutational patterns, however a new S42G variant was observed. The in vivo selection of S42G suggests that it might play a role in enfuvirtide resistance. Therefore, it could be considered as a candidate mutation to be included within drug resistance interpretation systems.

Topics: Amino Acid Sequence; Amino Acid Substitution; Anti-HIV Agents; Drug Resistance, Viral; Enfuvirtide; Evolution, Molecular; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation, Missense; Peptide Fragments; Salvage Therapy; Sequence Analysis, DNA; Treatment Failure

The synthetic peptide T-20 (enfuvirtide, EFV) represents the first compound approved by the FDA known as entry inhibitors (EIs). The resistance mutations associated with this new class of antiretroviral drug are located in the first heptad repeat (HR1) region of gp41. Amino acid changes in codons G36D/S, I37V, V38A/M/E, Q39H/R, Q40H, N42T, and N43D can confer resistance to EFV. In this work we investigated the presence of resistance mutations that occur in patients never treated with EFV and failing HAART with protease inhibitors (PIs), nucleoside reverse transcriptase (RT) inhibitors (NRTIs), and nonnucleoside RT inhibitors (NNRTIs). This knowledge can reveal whether this salvage therapy can be effective in patients failing HAART. For this, we amplified 65 samples from plasma isolates and than sequenced a fragment of 416 nt encompassing the HR1 and HR2 regions (amino acids 33-170 of gp41). The subtype distribution among the 65 isolates was 45 (69.23%) subtype B, 9 (13.85%) subtype C, 7 (10.77%) subtype F1, and 4 (6.15%) mosaics B/F1, B/C, F1/C, and C/F1/B. We found a high prevalence (7.6%) of EFV-associated mutation G36D in this cohort of patients failing HAART therapy, five isolates from subtype B (11.11% within this group). In contrast, when 1079 sequences from drug-naive patients were analyzed, only one showed the G36D substitution. This finding indicates a strong association between the selected position G36D and HAART therapy (p < 0.0001). The isolates that possess these mutations can develop resistance to EFV more rapidly. Nevertheless, more information about the impact of these mutations in salvage therapy with EFV in patients failing HAART must still be obtained.

Topics: Adult; Amino Acid Sequence; Amino Acid Substitution; Antiretroviral Therapy, Highly Active; Brazil; Drug Resistance, Viral; Enfuvirtide; Genotype; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Middle Aged; Molecular Sequence Data; Mutation, Missense; Peptide Fragments; Sequence Alignment; Sequence Analysis, DNA; Treatment Failure; Young Adult

For intensively pretreated pediatric patients with human immunodeficiency virus type 1 (HIV-1) infection, the treatment options available are limited. We report the case of a highly treatment-experienced 12-year-old boy with multidrug-resistant HIV-1, who was successfully treated with highly active antiretroviral therapy (HAART) including ritonavir-boosted tipranavir oral solution, a novel non-peptic protease inhibitor, and enfuvirtide.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Peptide Fragments; Pyridines; Pyrones; Remission Induction; Ritonavir; Sulfonamides; Treatment Outcome

Enfuvirtide is beneficial in patients with limited treatment options. We report this case to highlight the possibility of a delayed hypersensitivity reaction as an important potential side-effect of enfuvirtide treatment. A highly antiretroviral treatment-experienced man was commenced on a new regimen containing enfuvirtide. Prophylaxis for Pneumocystis jirovecii pneumonia was started using trimethoprim/sulphamethoxazole (TMP-STX) simultaneously. Ten days later, he developed a maculopapular rash on the chest and abdomen without any systemic features. Both enfuvirtide and TMP-STX were discontinued. Re-introduction of enfuvirtide occurred in a hospital setting. Before re-challenge, haemodynamic observations were stable. The rash re-appeared involving the whole body 5 hours post-dose and was associated with fever (temperature 38.4), nausea and a presyncopal episode. Hypersensitivity to this drug occurred immediately post-dose in phase III trials. Enfuvirtide is a useful drug in those with reduced drug options. The possibility of delayed hypersensitivity has not been reported previously.

Topics: Antiretroviral Therapy, Highly Active; Drug Hypersensitivity; Enfuvirtide; Exanthema; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Hypersensitivity, Delayed; Male; Middle Aged; Peptide Fragments

A substantial proportion of HIV-1 infected multidrug-resistant patients previously exposed to enfuvirtide (ENF) have recently recycled the drug as part of their optimized backbone therapy when starting a new antiretroviral regimen including investigational drugs, but no data are available concerning the impact of this strategy on clinical outcome. We evaluated long-term survival in multidrug-resistant patients recycling ENF after a previous failure.. A retrospective analysis of clinical outcomes in 32 multidrug-resistant patients receiving fewer than 3 active drugs who reintroduced ENF with those who did not.. Patients characteristics were not different in the 2 groups at the start of ENF treatment. During follow-up, 6 of the 15 patients (40%) who did not recycle ENF died, as did 3 of the 17 (17.7%) who recycled ENF. Survival probability was higher among patients who recycled ENF (P = 0.0006), also when the analysis was subdivided by CD4 cells gain (P = 0.003) or viral load decrease (P = 0.0003) at the end of the first cycle or the use of investigational drugs during follow-up (P = 0.003).. We found significantly longer survival in patients who reintroduced an ENF-containing regimen after a previous failure on the drug. We therefore suggest considering ENF recycling in patients starting a new regimen with fewer than 3 active drugs.

Topics: Adult; Anti-HIV Agents; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Long-Term Survivors; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Retrospective Studies

The Veterans Health Administration (VHA) develops guidelines for VHA providers that delineate specific criteria for use of certain complex, costly medications indicated for specialized populations. These criteria are disseminated to all VHA facilities.. To (a) assess the concordance with VHA guidelines for use of 4 antiretrovirals (atazanavir, darunavir, enfuvirtide, and tipranavir), and (b) to describe prescribing of these agents before and after implementation of the guideline criteria.. In this retrospective cohort study, we evaluated all veterans in VHA care who received their first outpatient prescription for a target antiretroviral between its FDA approval date and December 31, 2007, using outpatient prescription records obtained from the VHA Human Immunodeficiency Virus (HIV) Clinical Case Registry (CCR:HIV), an observational registry database created through extraction of specific clinical data from the VHA's electronic medical record. Adherence to the VHA guideline criteria was assessed using CCR:HIV data overall and during 3 time periods: (a) pre-criteria: from FDA approval date to criteria implementation date (range 38 days to 192 days), (b) early-criteria: the first 6 months after criteria implementation, and (c) late-criteria: from 180 days after criteria implementation until December 31, 2007 (range 184 days to 1,525 days).. VHA providers prescribed target antiretroviral medications in accordance with the VHA guidelines for use more than 70% of the time. Comparing the pre-criteria with the post-criteria period (i.e., early-criteria and late-criteria combined), no significant differences in the percentages of veterans satisfying all VHA criteria were observed for any drug except atazanavir (P = 0.010). For atazanavir in the post-criteria period compared with the pre-criteria period, significantly more antiretroviral-naive veterans met criteria for cardiovascular disease or risk (72.8% post-criteria vs. 45.5% pre-criteria, P = 0.045), and significantly more antiretroviral-experienced veterans met criteria for resistance to other protease inhibitors requiring the need for ritonavir-boosted atazanavir (61.7% vs. 50.5%, respectively, P < 0.001); however, fewer antiretroviral-experienced veterans met criteria for having documented intolerance to other protease inhibitors (78.9% vs. 89.9%, respectively, P < 0.001). Fewer darunavir-treated patients in the post-criteria period than in the pre-criteria period met the criteria for treatment experience including failure of at least 1 prior protease inhibitor regimen (87.8% vs. 96.0%, respectively, P = 0.002). Adherence to all darunavir criteria significantly waned over time (early-criteria 78.8% vs. late-criteria 62.5%, P < 0.001). Overall, adherence to atazanavir criteria increased over time (66.3% early-criteria vs. 72.9% late-criteria, P < 0.001).. After implementation of antiretroviral specific guideline criteria, the proportion of veterans prescribed a target antiretroviral medication in accordance with VHA guideline criteria varied by agent and improved only for atazanavir. Although adherence to criteria for atazanavir, enfuvirtide, and tipranavir persisted or improved during the post-criteria period, darunavir adherence to criteria waned over time, perhaps indicating that later prescribing patterns reflected changing practice patterns and the need for updated criteria. Revisiting and updating criteria may be especially important for HIV due to the speed with which new information becomes available.

Topics: Anti-Retroviral Agents; Atazanavir Sulfate; Darunavir; Enfuvirtide; Guideline Adherence; Guidelines as Topic; Health Plan Implementation; HIV Envelope Protein gp41; HIV Infections; Humans; Oligopeptides; Peptide Fragments; Practice Patterns, Physicians'; Pyridines; Pyrones; Retrospective Studies; Sulfonamides; Time Factors; United States; United States Department of Veterans Affairs

Primary mutations in HIV-1 that are directly involved in the resistance to enfuvirtide have been well documented. However, secondary mutations that are associated with primary mutations and contribute little to the resistance still remain to be elucidated. This study reveals that synonymous mutations at gp41 Q41 (CAG to CAA) or L44 (UUG to CUG) act as secondary mutations. Complementary mutations in the nucleotide level are located in the Rev responsive element (RRE) of the HIV-1 RNA-genome and maintain the replication kinetics of HIV-1 through increasing the structural stability of stem-loop III in the RRE. Therefore, synonymous mutations in the gp41/RRE sequence improve the viral replication impaired by the primary mutations and play a key role as secondary (complementary) mutations.

Topics: Anti-HIV Agents; Cell Line; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Peptide Fragments; Point Mutation; rev Gene Products, Human Immunodeficiency Virus; Virus Replication

Although Enfuvirtide (T20) has not been used in China, investigating the natural occurrence of primary resistance mutations in the HR1 region of the gp41 sequence from T20 naïve patients would help in determining treatment strategies for AIDS patients.. To investigate natural mutations in the HR1 region of the gp41 sequence in China and evaluate their biological function.. The amino acid sequences in the HR1 region of 27 isolates including subtypes AE, BC and B' from Chinese T20 naïve patients were analyzed. All 27 isolates were constructed into pseudoviruses and their susceptibility to T20 was measured by using recombinant virus assays.. Mutations in a 10 amino acid motif, such as N42S and N42R, and those outside this motif, such as L33M, R46S, A50V, Q52H and L54M, were found in the 27 isolates. N in position 42 was mutated to S in all three AE subtype strains and 17 of 18 subtype BC strains, whilst it was mutated to R in all 6 subtypes B strains. Compared to the SF162 strain, the susceptibility of the mutants, except for L33M, to T20 was not significantly different. After L was mutated to M in position 33 of six strains by site directed mutagenesis, their IC50 values were increased by 3.7-7.9-fold.. Mutations outside a 10 amino acid motif in HR1, such as L33M, may cause T20 resistance.

Topics: Amino Acid Sequence; Amino Acid Substitution; Anti-HIV Agents; China; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Inhibitory Concentration 50; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation, Missense; Peptide Fragments; Sequence Analysis, DNA

T20 (generic name, enfuvirtide; brand name, Fuzeon) is a first-generation human immunodeficiency virus (HIV) fusion inhibitor approved for salvage therapy of HIV-infected patients refractory to current antiretroviral drugs. However, its clinical use is limited because of rapid emergence of T20-resistant viruses in T20-treated patients. Therefore, T1249 and T1144 are being developed as the second- and third-generation HIV fusion inhibitors, respectively, with improved efficacy and drug resistance profiles. Here, we found that combinations of T20 with T1249 and/or T1144 resulted in exceptionally potent synergism (combination index, <0.01) against HIV-1-mediated membrane fusion by 2 to 3 orders of magnitude in dose reduction. Highly potent synergistic antiviral efficacy was also achieved against infection by laboratory-adapted and primary HIV-1 strains, including T20-resistant variants. The mechanism underlying the synergistic effect could be attributed to the fact that T20, T1249, and T1144 all contain different functional domains and have different primary binding sites in gp41. As such, they may work cooperatively to inhibit gp41 six-helix bundle core formation, thereby suppressing virus-cell fusion. Therefore, these findings strongly imply that, rather than replacing T20, combining it with HIV fusion inhibitors of different generations might produce synergistic activity against both T20-sensitive and -resistant HIV-1 strains, suggesting a new therapeutic strategy for the treatment of HIV-1 infection/AIDS.

Topics: Amino Acid Sequence; Cell Line; Drug Combinations; Drug Resistance, Viral; Drug Synergism; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Membrane Fusion; Molecular Sequence Data; Peptide Fragments

Partial-treatment interruption in patients with drug-resistant viremia has been associated with stable HIV RNA levels suggesting that interruption of protease inhibitors may be an effective strategy for patients without other therapeutic options while waiting for the development of new drugs.. Our goal was to maintain virological and immunological stability in patients experiencing virologic failure with multiresistant HIV to allow access to newly developed antiretroviral drugs, and to characterize the impact of partial-treatment interruption on replication capacity and resistance profile.. From 2003 to 2004, a group of 12 heavily treated patients was studied. Protease inhibitor treatment was interrupted and patients were treated with nucleoside analog retrotranscriptase inhibitors (Trizivir) and the fusion inhibitor Enfurvirtide to establish the therapeutic benefit and the virologic response.. Both, CD4 T-cell counts and viral load remained stable for a period of time that enabled all the patients to access rescue treatments (median=13.5 months; IQR: 9-19). The replication capacity of the patient-derived viruses significantly decreased or remained stable during the partial-treatment interruption. The decrease in replication capacity was mainly attributable to the selection of viruses carrying at least two fewer minor mutations in the protease. As of December 2008 10 of 12 patients maintained undetectable HIV RNA levels.. Study results indicate that a partial-treatment interruption regimen based on Trizivir with Enfurvirtide augmentation allows for a loss of protease inhibitor resistance mutations as well as for a decrease in the replication capacity of patient-derive HIV protease gene recombinants.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Drug Combinations; Drug Resistance, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Middle Aged; Peptide Fragments; Treatment Outcome; Viral Load; Withholding Treatment; Zidovudine

We analyzed HIV gp41 from 195 men in the United States who were HIV-1 infected between 1999 and 2002, before enfuvirtide (ENF) was approved for clinical use in the United States. gp41 genotyping results were obtained for 175 samples. None of the samples had major ENF resistance mutations. Six (3.4%) samples had minor ENF resistance mutations in the HR1 region (V38G, N43K, L44M, L45M). Twenty-eight (16%) samples had the N42S polymorphism, which is associated with ENF hypersusceptibility. Accessory mutations in the HR2 region were identified in some samples (E137K, S138A). Five of the six samples with HR1 resistance mutations were analyzed with a phenotypic assay; one sample had reduced ENF susceptibility (a sample with N42S +L44M + E137K). Prior to the availability of ENF, some men in the United States were infected with HIV that contained mutations associated with ENF resistance or hypersusceptibility. However, most of the mutations were not associated with phenotypic ENF resistance.

Topics: Amino Acid Substitution; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Peptide Fragments; Polymorphism, Genetic; RNA, Viral; Sequence Analysis, DNA; Time Factors; United States

Topics: Adult; Canada; CD4 Lymphocyte Count; Cohort Studies; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Treatment Outcome; Viral Load

In previous studies on mechanisms of HIV-1-mediated pathogenesis we showed that bystander apoptosis mediated by cell surface-expressed HIV-1 Env correlated with the fusogenic properties of the gp41 subunit of Env. A crucial step in HIV gp41-mediated fusion is the refolding of the protein into a six-helix bundle along the N- and C-terminal coiled-coil domains. These domains have been targeted by peptide inhibitors that inhibit gp41-mediated fusion. One of these inhibitors, enfuvirtide, is the first such drug approved for therapy. More recently, clinical data suggest that the beneficial effects of enfuvirtide extend beyond virus suppression and are associated with certain resistance mutations in gp41. In this study we characterized the bystander apoptosis-inducing potential of mutants associated with increased CD4 counts that arise during enfuvirtide therapy. Whereas all mutant clones were reduced in both cell-to-cell fusion activity and apoptosis induction there was limited effect on virus infection or replication. The viruses were found to have apoptosis-inducing activity in the order WT > V38M > V38A > G36D > V38E, which correlated with cell-to-cell fusion but not infection. Interestingly, the level of resistance as determined by the IC(50) of enfuvirtide also correlated inversely with both cell fusion and apoptosis in that the most resistant Envs were the least fusogenic and pathogenic. This suggests the beneficial effects of enfuvirtide therapy beyond virus suppression may be mediated by selecting less pathogenic HIV isolates over time.

Topics: Amino Acid Substitution; Apoptosis; CD4-Positive T-Lymphocytes; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Mutation; Peptide Fragments

The development of antiviral drugs has provided crucial new means to mitigate or relieve the debilitating effects of many viral pathogens. Regular use of these drugs has led to generation of resistant strains, making the control of many viral infections very difficult, particularly in HIV-seropositive and AIDS patients. A rich source for the discovery of new HIV infection inhibitors has been, and continues to be, the 'mining' of the large diversity of compounds already available in nature, and specifically those from botanical extracts.. Using a newly developed direct binding assay with mass spectrometry technology (direct analysis in real-time time-of-flight mass spectrometry), we were able to show that compounds present in extracts of elderberry, cinnamon and green tea bind to and block HIV type-1 (HIV-1) infection in target cells.. The compounds that blocked HIV-1 infection were flavonoids and A-type proanthocyanidins. The 50% inhibitory concentration values of these extracts ranged from 0.5 to 201 microg/ml for four different HIV-1 serotypes. Interaction matrices with the elderberry extract and enfuvirtide, a peptide HIV-1 fusion inhibitor, revealed significant super additive effects. This indicates that the compounds in elderberry that prevent HIV-1 infection are likely to bind to viral glycoproteins other than gp41 (the binding site for enfuvirtide).. Optimized elderberry, green tea and cinnamon extracts rich in certain flavonoid compounds were shown to block HIV-1 entry and infection in GHOST cells. As such, these types of botanical extracts could provide a starting point for the development of possible safe and reliable cotherapies for HIV-1-positive individuals, as well as for the identification of new small molecules as leading drug candidates for HIV-1 therapeutics and microbicides.

Topics: Anti-HIV Agents; Binding Sites; Camellia sinensis; Catechin; Cell Line, Tumor; Cinnamomum zeylanicum; Dose-Response Relationship, Drug; Drug Discovery; Drug Synergism; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Mass Spectrometry; Peptide Fragments; Plant Extracts; Reproducibility of Results; Sambucus; Time Factors; Virion; Virus Internalization

HIV-1 resistance mutations to antiretroviral (ARV) drugs (nucleoside reverse transcriptase inhibitors, NRTI; nonnucleoside reverse transcriptase inhibitors, NNRTI; and protease inhibitors, PI) represent a challenge for sustainable virologic and immunologic responses. HIV-1 phylogenetic diversity and ARV resistance mutations associated with protease (PR) and reverse transcriptase (RT) were assessed among 48 ARV-experienced patients from Goiania/Goias, central west Brazil. The gp41 resistance mutations to the fusion inhibitor (T-20) were analyzed among multidrug-resistant (MDR) patients. PR, partial RT, and gp41 genes were amplified and sequenced from plasma RNA. HIV-1 subtype was assigned by phylogenetic analysis. ARV mutations in PR/RT were analyzed by the Stanford Database. T-20 resistance mutations in gp41 were identified by Stanford, the Los Alamos Database, and other sources. Subtype B represented 79.2% (38/48), subtype F1 4.2% (2/48), subtype C 2.1% (1/48), F1(PR)/B(RT) 8.3% (4/48), and B(PR)/F1(RT) 6.3% (3/48). Secondary drug resistance was observed in 79% (38/48): NRTI resistance (n = 1), NNRTI resistance (n = 1), PI + NRTI or NRTI + NNRTI resistance (n = 20), and PI + NRTI +NNRTI resistance, considered MDR (n = 16). Almost half of the MDR patients had viral loads below 10,000 copies/ml. The gp41 sequences from 14 MDR revealed one F1(PR)/B(RT)/F1(ENV) recombinant and 13 subtype B(PR)/B(RT)/B(ENV) isolates. G36E, N42T, and N43S T-20 resistance mutations were observed in three MDR patients, two of them previously treated with T-20 and the other who had never used T-20. Our data among ARV-experienced patients showed a high proportion of drug-resistance mutations and MDR. T-20 resistance mutations were detected among MDR patients corroborating the importance of T-20 genotyping for clinical management and salvage therapy.

Topics: Adolescent; Adult; Anti-HIV Agents; Brazil; Child; Drug Resistance, Multiple, Viral; Enfuvirtide; Female; Genotype; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Middle Aged; Molecular Sequence Data; Mutation, Missense; Peptide Fragments; Phylogeny; pol Gene Products, Human Immunodeficiency Virus; RNA, Viral; Sequence Analysis, DNA; Young Adult

Raltegravir is a potential treatment option for virologically suppressed HIV-1 infected patients on enfuvirtide with injection site reactions.. To characterize safety and efficacy of an enfuvirtide to raltegravir switch including changes in T-cells, quality of life, and residual viremia.. In patients with viral load <50 copies/mL and injection site reactions, enfuvirtide was switched to raltegravir without additional changes to the antiretroviral regimen. Virologic failure was defined as a viral load >1000 copies/mL or two consecutive viral load measurements between 50 and 1000 copies/mL (low-level viremia). Over the 24 week study, we compared changes in T-cells, injection site reactions, quality of life, and residual viremia, as measured through the single-copy assay which can detect plasma virus down to a single copy, using paired t-tests.. Fourteen patients with a median CD4+ T-cell count of 420 cells/microL were enrolled. After the switch, two patients experienced virologic failure due to confirmed low-level viremia. However, both patients subsequently were re-suppressed, one without any changes to his regimen. There was no change in CD4+ T-cell count. Injection site reactions resolved. However, there was little reported change in quality of life. The baseline median level of residual viremia was 6 copies/mL and did not change after the switch to raltegravir.. A switch to raltegravir in virologically suppressed patients on enfuvirtide is effective in maintaining immunologic and virologic control at 24 weeks but did not result in a change in residual viremia.

Topics: CD4 Lymphocyte Count; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Prospective Studies; Pyrrolidinones; Quality of Life; Raltegravir Potassium; Treatment Outcome; Viral Load; Viremia

In recent years, novel antiretroviral drugs have become available for multi-experienced HIV-infected patients with limited options. We enrolled seven advanced HIV-patients, failing multiple previous HAART regimens, in virological failure on their current HAART regimen and showing recent clinical and immunological progression. All patients were prescribed a double-boosted tipranavir plus enfuvirtide based regimen, in addition to zidovudine, tenofovir and lamivudine for salvage therapy. To assess susceptibility to tipranavir, the tipranavir genotypic resistance score was calculated and two years later this was re-evaluated on an updated tipranavir genotypic score algorithm. At baseline, CD4 were 139/mcL (more or less 145), HIV-1 RNA was 822,700 cp/mL. All patients achieved HIV-1 RNA levels less than 400 cp/mL between 12 weeks and 24 weeks of observation; two reached less than 50 cp/mL during this period. At 48 weeks three patients had reached less than 50 cp/mL; three other patients had HIV RNA less than 200 cp/mL. At 72 and 96 weeks HIV viraemia was less than 50 cp/mL in six patients; CD4 T-cell counts 285/mcL (more o less 198). No AIDS-defining events were recorded. Adverse events did not need to stop or change HAART. Strong 3 NRTI backbone could help efficacy and durability, and frequent evaluations in complex patients can help to manage toxicity.

Topics: Adult; Algorithms; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease Progression; Enfuvirtide; Female; Follow-Up Studies; Genotype; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Mutation; Peptide Fragments; Phenotype; Pyridines; Pyrones; Salvage Therapy; Sulfonamides; Time Factors; Treatment Outcome

Enfuvirtide has been a cornerstone of salvage therapy for multidrug-resistant HIV. Raltegravir provides another novel class option, with the advantages of easier administration and improved tolerability. Thirty-five adults electively replaced enfuvirtide with raltegravir while the rest of their regimen was unchanged. All maintained virologic suppression after a median of 7 months except one who experienced a transiently detectable viral load after 5 months. The new regimen was well tolerated with no apparent new drug-related adverse clinical or laboratory events.

Topics: Adult; Aged; Drug Resistance, Multiple, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

Enfuvirtide is a potent inhibitor of systemic HIV-1 replication, but its penetration into the human central nervous system (CNS) has not been analysed. Here, we define cerebrospinal fluid (CSF) enfuvirtide pharmacokinetics and present a case illustrating the use of enfuvirtide as a probe to trace the origins of CSF HIV-1 quasispecies.. Enfuvirtide CSF pharmacokinetics were assessed in 18 CSF and plasma sample pairs from four HIV-1-infected individuals. Enfuvirtide levels were measured by liquid chromatography tandem mass spectrometry using known standards and controls that included spiked CSF samples from untreated, HIV-negative individuals. A segment of the gp41 coding region encompassing the heptad repeat HR-1 and HR-2 domains was amplified from selected CSF and plasma samples and independent clones sequenced to assess resistance-associated mutations.. CSF and plasma samples obtained between 2 and 20 h after enfuvirtide injection showed plasma concentrations similar to previous reports (mean 3.687 SD +/- 1.828 mg/ml) with prolonged decay. By contrast, enfuvirtide in all CSF samples was below the assay detection limit of 0.025 mg/ml. In one individual, who developed a transient increase in CSF HIV-1 RNA, seven of seven CSF and plasma clones had identical enfuvirtide resistance-associated V38A mutations, suggesting that the CSF quasispecies derived from that of blood.. Enfuvirtide penetration into CSF is negligible; thus, in clinical settings, where direct CNS drug exposure is crucial, this drug Is not likely to directly contribute to the local therapeutic effect. Enfuvirtide can be used as a tool to dissect the origin of the CNS virus.

Topics: Adult; AIDS Dementia Complex; Blood-Brain Barrier; Chromatography, Liquid; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Longitudinal Studies; Middle Aged; Mutation; Peptide Fragments; RNA, Viral; Tandem Mass Spectrometry

To estimate the in vivo fitness cost of enfuvirtide (ENF) resistance, we analyzed dynamic shifts in the HIV-1 quasispecies under changing selective pressure in 3 subjects on failing ENF-based regimens who interrupted ENF while maintaining stable background regimens. Subsequently, ENF was readministered for 4 weeks as "pulse intensification.". The proportion of plasma virus carrying the V38A mutation in gp41 was quantified by allele-specific real-time polymerase chain reaction in serial samples collected from 3 subjects at 1- to 4-week intervals. Fitness differences were calculated using a method that corrected for time dependence of the viral replication rate.. The V38A mutant made up >or=85% of the quasispecies at baseline and decayed to <5% over 12-24 weeks; plasma HIV-1 RNA levels remained stable during this time. Fitness differences for mutant versus wild type ranged from -25% to -65%, providing in vivo evidence for the reduced fitness of ENF-resistant HIV-1. The V38A mutant virus reemerged rapidly during the ENF pulse.. These results demonstrate that the HIV-1 quasispecies undergoes dynamic changes in response to withdrawal and reinitiation of fusion inhibitor therapy. The relative stability of plasma HIV-1 titers during decay of V38A suggests that factors other than viral fitness likely define viral load set-point in patients with advanced disease.

Topics: Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Mutation; Peptide Fragments; Viral Load

Neurokinin-1 receptor (NK-1R) antagonists suppress HIV-1 infection of macrophages in vitro. We have further investigated the anti-HIV-1 activity of aprepitant, a Food and Drug Administration-approved NK-1R antagonist, and its cytotoxic effect in the macrophage/microglia system. Aprepitant inhibited infection of macrophages with primary HIV-1 R5 strains (subtypes A, D, and H; UG275, BZ163, and BCF-KITA), while it had little effect on primary HIV-1 X4 strains (subtypes B and D, BZ167 and SE365). Aprepitant, when added to microglia cultures infected with CSF-derived HIV-1 strains (JAGO or JRFL), significantly inhibited viral replication. Aprepitant also enhanced the anti-HIV-1 activity of enfuvirtide (an HIV-1 fusion inhibitor) in HIV-1-infected macrophages. Over a concentration range of 10(-9) to 10(-5) M, aprepitant had little cytotoxic effect (less than 10%) on macrophages during the in vitro cultures. Autologous human serum (< or =20%) had little effect on the anti-HIV-1 activity of aprepitant in macrophages. These observations provide additional evidence to support the potential use of NK-1R antagonists as therapeutic and immunomodulatory agents for the treatment of HIV-1 infection.

Topics: Antiviral Agents; Aprepitant; Cells, Cultured; Drug Synergism; Enfuvirtide; Flow Cytometry; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Macrophages; Microglia; Morpholines; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Virus Replication

Enfuvirtide is the first fusion inhibitor approved for use in HIV treatment and is a useful therapeutic option for highly treatment experienced individuals. Passive reporting has associated increased neuropathy rates with enfuvirtide use in some early studies but not others. The aim of this study was to describe any functional or clinical changes consistent with neuropathy among enfuvirtide users. A prospective cohort study of patients commencing or continuing enfuvirtide at a state HIV referral service, including clinical and sensory threshold monitoring, was conducted. A total of 14 patients were studied. All had advanced HIV disease and 13 (93%) had symptoms and/or signs consistent with neuropathy at baseline. Patients who entered the study on enfuvirtide-based therapy remained neurologically stable throughout follow-up. Eleven patients were assessed preand postenfuvirtide. No evidence was found for any clear effect of enfuvirtide on neuropathic symptoms, neuropathic signs, or sensory thresholds at a cohort level (p > 0.3 for all, Wilcoxon signed rank test). However, three (21%) patients experienced worsening of existing neuropathy symptoms (transient in two cases) and two (14%) patients' symptoms improved with enfuvirtide commencement. Breakthrough HIV viremia was associated with worsening symptoms in two patients at 5 and 18 months of enfuvirtide use. This study found no clear effect on peripheral nerves from enfuvirtide. Although limited by a small sample size, this study involved patients who would have been particularly vulnerable to a neurotoxin, with advanced HIV disease and a high rate of baseline neurological abnormalities. We observed no clear evidence of neurotoxicity from enfuvirtide in this population.

Topics: Adult; Aged; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Middle Aged; Peptide Fragments; Peripheral Nervous System Diseases; Prospective Studies

The availability of antiretroviral therapy has dramatically reduced the risk of HIV mother-to-child transmission (MTCT). However, mothers infected with multidrug resistant HIV (MDR-HIV) are at increased risk of MTCT. We report the case of a pregnant patient infected with MDR-HIV in whom MTCT was avoided with enfuvirtide use in late pregnancy and elective caesarean section.

Topics: Adult; CD4 Lymphocyte Count; Cesarean Section; Drug Resistance, Multiple, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Peptide Fragments; Pregnancy; Pregnancy Complications, Infectious; Treatment Outcome

Enfuvirtide (Fuzeon) is the first self-injectable antiretroviral (ARV) therapy approved for the treatment of HIV. This study was undertaken to explore the perceptions of injectable ARVs among physicians and treatment-experienced HIV-infected patients and identify potential motivators or barriers to the initiation of injectable ARV therapies. This empirical study was conducted based on qualitative field research conducted in multiple centres in five European countries and the US. A purposive sampling strategy was employed and structured interviews carried out with physicians and patients. Discussion guides for these interviews focused on attitudinal responses to a range of key areas. For physicians, these areas included HIV treatment, treatment-experienced patients and their relationships with them and injectable therapy usage, while for patients - some of whom were receiving enfuvirtide therapy - the focus included relationships with their physicians and attitudes towards injectable ARV therapy. Sixty-eight physicians and 43 patients were interviewed. Qualitative analysis of the interview responses revealed a number of recurring themes among physician and patient perceptions of HIV and its treatment. Physicians tended to view injectable ARVs as a last resort, with only limited suitability among treatment-experienced patients and a low level of patient acceptability. In contrast, patients generally perceived the potential value of effective injectable ARV therapy, if recommended to them by their physicians, indicating that its benefits could outweigh the drawbacks associated with its administration. This study identified some potential disconnects between physician and patient perceptions of injectable therapy. Our findings emphasize the need for patients to discuss their treatment goals with their physicians so that they can work together to find the regimen that is most likely to achieve these goals.

Topics: Adult; Aged; Communication; Disease Progression; Drug Administration Schedule; Enfuvirtide; Female; Health Knowledge, Attitudes, Practice; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Injections, Subcutaneous; Male; Middle Aged; Patient Compliance; Peptide Fragments; Physician-Patient Relations; Physicians; Self Administration

We conducted subanalyses of the combined results of the Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2 studies to better characterize the efficacy and safety of maraviroc in key subgroups of patients.. We analyzed pooled data from week 48 from the two studies according to sex, race or ethnic group, clade, CC chemokine receptor 5 (CCR5) delta32 genotype, viral load at the time of screening, the use or nonuse of enfuvirtide in optimized background therapy (OBT), the baseline CD4 cell count, the number of active antiretroviral drugs coadministered, the first use of selected background agents, and tropism at baseline. Changes in viral tropism and the CD4 count at treatment failure were evaluated. Data on aminotransferase levels in patients coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV) were also analyzed.. A treatment benefit of maraviroc plus OBT over placebo plus OBT was shown in all subgroups, including patients with a low CD4 cell count at baseline, those with a high viral load at screening, and those who had not received active agents in OBT. Analyses of the virologic response according to the first use of selected background drugs showed the additional benefit of adding a potent new drug to maraviroc at the initiation of maraviroc therapy. More patients in whom maraviroc failed had a virus binding to the CXC chemokine receptor 4 (CXCR4) at failure, but there was no evidence of a decrease in the CD4 cell count at failure in such patients as compared with those in whom placebo failed. Subanalyses involving patients coinfected with HBV or HCV revealed no evidence of excess hepatotoxic effects as compared with baseline.. Subanalyses of pooled data from week 48 indicate that maraviroc provides a valuable treatment option for a wide spectrum of patients with R5 HIV-1 infection who have been treated previously. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)

Topics: Adult; Aged; Anti-Retroviral Agents; CCR5 Receptor Antagonists; CD4 Lymphocyte Count; Cyclohexanes; Double-Blind Method; Drug Therapy, Combination; Enfuvirtide; Ethnicity; Female; Genotype; Hepatitis B; Hepatitis C; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Maraviroc; Middle Aged; Odds Ratio; Peptide Fragments; Receptors, CCR5; RNA, Viral; Transaminases; Treatment Outcome; Triazoles; Viral Load

Most enfuvirtide outcomes data come from controlled trials of limited duration rather than from routine experience. Because of its uniqueness, the Veterans Health Administration (VHA) implemented specific enfuvirtide prescribing and follow-up criteria (criteria for use; CFU) and then assessed providers' compliance with these criteria and outcomes.. To report routine medical care experience with the prescribing, efficacy, and tolerability of enfuvirtide in a nonselective group of treatment-experienced, older, HIV-infected veterans.. Veterans receiving at least one outpatient prescription for enfuvirtide between April 2003 and July 2005 were identified from the VHA's HIV Clinical Case Registry (CCR:HIV). Targeted retrospective chart extraction was completed to address inclusion/exclusion criteria and to evaluate patients' continued use, adherence, and tolerance. CCR:HIV data were used for determination of demographics, prescription records, and laboratory results. The final cohort was used to assess providers' compliance with VHA's CFU for enfuvirtide.. Of 275 evaluable subjects, between 52% and 93% who were prescribed enfuvirtide met each VHA CFU. Median change in CD4 cells and viral load from baseline to 6 months was +39 cells/mm(3) and -0.79 log(10) (p < 0.001) and at 2 years was +72 cells/mm(3) and -1.57 log(10) (p < 0.001); 41% and 55% of veterans achieved viral load less than 400 copies/mL at 6 months and 2 years, respectively. Seventy percent of veterans experienced injection site reactions (11% were treatment-limiting). New or worsening adverse effects occurred in 56% of veterans: 32% gastrointestinal, 19% musculoskeletal, and 10% respiratory. Seventy percent of veterans discontinued enfuvirtide within 2 years; the largest portion (12%) stopped treatment within the first month. Documented reasons for discontinuation included patient request (42%), suboptimal response/progression (24%), toxicity (18%), death (13%), and transfer of care outside of the VHA (3%).. In this treatment-experienced veteran cohort, providers prescribed enfuvirtide in accordance with most CFU, and favorable treatment responses were sustained in patients able to remain on therapy. Challenges that providers and patients face include ongoing education and support for successful long-term use.

Topics: Adult; Cohort Studies; Drug Administration Schedule; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Middle Aged; Patient Compliance; Peptide Fragments; Practice Patterns, Physicians'; Product Surveillance, Postmarketing

The new non-peptidic protease inhibitor tipranavir is used boosted with ritonavir in a 500/200 mg bid scheme. Multiple drug interactions are described for both drugs because of their different action in CYP450 3A4 and p-glycoprotein. In this retrospective analysis of 22 patients during therapy with tipranavir/ritonavir (TPV) 500 mg/200 mg bid, we found significantly decreased TPV-trough levels in combination with tenofovir (15.32+/-5.22 microg/ml) in comparison to TPV trough levels without tenofovir (20.21+/-14.87 microg/ml). Therapeutic drug monitoring of TPV is recommended.

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Interactions; Drug Monitoring; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Organophosphonates; Peptide Fragments; Pyridines; Pyrones; Retrospective Studies; Ritonavir; Sulfonamides; Tenofovir

A 41-year-old pregnant woman with multiple virological failures started darunavir, enfuvirtide, zidovudine and lamivudine at week 28 of pregnancy. During week 38, the patient had a viral load <400 copies/mL and a CD4 count of 180 cells/mm(3) (13%). The child was found to be in good health, with negative HIV-polymerase chain reactions at birth, at two and at six months.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Darunavir; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant, Newborn; Peptide Fragments; Pregnancy; Pregnancy Outcome; Sulfonamides; Treatment Outcome; Viral Load

We present a model of the pharmacokinetics of enfuvirtide, a potent inhibitor of the fusion of human immunodeficiency virus type 1 (HIV-1) with target cells. We assume that subcutaneously administered enfuvirtide accumulates in the injection region, diffuses locally, and gets absorbed into blood, where it reversibly associates with lipidic cell membranes and is eventually eliminated. We develop mathematical descriptions of each of these processes and predict the time-evolution of the concentration of enfuvirtide in plasma, C(p). We find, interestingly, that diffusion of enfuvirtide in the subcutaneous region is decoupled from absorption, which enables deduction of analytical expressions for C(p) following single dose administration and ordinary differential equations following multiple dose administration and renders our model amenable to data analysis. Model predictions provide excellent fits to observed plasma concentration-time profiles of enfuvirtide following the intravenous and subcutaneous administration of a single dose and without any adjustable parameters capture quantitatively concentration-time profiles following the administration of multiple doses. Our model thus presents a robust description of the pharmacokinetics of enfuvirtide and may be applied in conjunction with models of viral dynamics to assess responses of HIV-1 patients to alternative enfuvirtide-based therapies. Further, our model reveals that key pharmacokinetic characteristics of enfuvirtide, viz., steady state values of peak and trough concentrations and area under the concentration-time curve, vary nearly linearly with dosage over a broad range of dosages and for different dosing regimens, which enables a priori estimation of enfuvirtide exposure levels for different treatment protocols and may serve to establish guidelines for therapy optimization.

Topics: Area Under Curve; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Injections, Intravenous; Injections, Subcutaneous; Models, Biological; Peptide Fragments; Therapeutic Equivalency; Time Factors

HIV-1 cell-to-cell transmission is more efficient than infection of permissive cells with cell-free particles. The potency of HIV-1 entry inhibitors to inhibit such transmission is not well known. Herein, we evaluated the efficacy of this new class of antiretrovirals to block cell-to-cell transmission of HIV-1 in a model of reconstitution of the human placental trophoblast barrier in vitro.. Our data show that CCR5 antagonists and T20 inhibit the passage of the virus across the BeWo cell monolayer in contact with PBMCs infected with an R5 (Ba-L) and a dualtropic (A204) HIV-1 with IC50s in the range of 100 - 5,000 nM for TAK779; 90 to 15,000 nM for SCH-350581 and 3,000 to 20,000 nM for T20. The CXCR4 antagonist AMD3100 is also effective against X4 HIV-1 infected PBMCs in our model with IC50 comprised between 4 nM and 640 nM. HIV-1 entry inhibitors are less efficient to block cell-to-cell virus transmission than cell-free HIV-1 infection of PBMCs and CCR5 antagonists do not prevent PBMC infection by dual tropic HIV-1 in contrast to cell-to-cell infection in our model.Surprisingly, T20 (and C34) do not block cell-to-cell transmission of X4 HIV-1 but, rather, increase 80 to 140 fold, compared to control without drug, the passage of the virus across the trophoblast barrier. Additional experiments suggest that the effect of T20 on BeWo/PBMC-X4 HIV-1 is due to an increase of effector-target cells fusion.. Our results support further evaluation of HIV-1 coreceptor antagonists, alone or combined to other antiretrovirals, in a perspective of prevention but warn on the use of T20 in patients bearing X4 HIV-1 at risk of transmission.

Topics: Benzylamines; CCR5 Receptor Antagonists; CD4-Positive T-Lymphocytes; Cell Communication; Cell Line; Cells, Cultured; Coculture Techniques; Cyclams; Enfuvirtide; Female; Heterocyclic Compounds; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Models, Biological; Niacinamide; Peptide Fragments; Piperazines; Placenta; Receptors, CXCR4; Trophoblasts; Virus Replication

Randomized clinical trials have demonstrated that enfuvirtide plus an optimized background regimen can cause a significant increase in CD4+ cell counts and a reduction in HIV RNA levels.. To describe and analyze CD4+ cell count and HIV RNA changes in HIV-infected patients receiving enfuvirtide and a prescribed background regimen (PBR) in a primarily clinical setting.. A retrospective review from September 1998 through August 2005 of CD4+ cell counts and HIV RNA changes from baseline was conducted in patients receiving enfuvirtide. Data were stratified and analyzed according to baseline CD4+ cell count and HIV RNA.. A mean CD4+ cell count increase of approximately 102 cells/mm(3)was observed, regardless of baseline CD4+ cell count, in 187 patients receiving enfuvirtide during a mean of 19.4 months of follow-up. During 3 years of follow-up, patients initiating enfuvirtide at CD4+ cell counts less than 100 cells/mm(3)never achieved absolute CD4+ cell counts comparable to the counts in patients starting enfuvirtide at CD4+ cell counts of 100 cells/mm(3)or more. In 38.3% of patients achieving an undetectable HIV RNA level, a mean CD4+ cell count increase of 185 cells/mm(3)was observed. An unexpected finding was that a mean CD4+ cell count increase of 76 cells/mm(3)occurred in 61.7% of patients not achieving complete viral suppression.. Immunologic benefits were observed in subjects continuing enfuvirtide plus a PBR irrespective of baseline CD4+ cell count, complete viral suppression, or antiretroviral susceptibility data. Data suggest that initiation of enfuvirtide at CD4+ cell counts greater than 100 cells/mm(3)may be immunologically advantageous and independent of complete virologic response.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Enfuvirtide; Follow-Up Studies; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Retrospective Studies; State Health Plans; Viral Load

Human immunodeficiency virus type 1 (HIV-1) gp41 is a crucial determinant for HIV-1 pathogenicity. We investigated the correlation of enfuvirtide (ENF)-associated gp41 mutational clusters with viroimmunological parameters, as well as the potential underlying mechanisms.. A total of 172 gp41 sequences and clinical follow-up data from 73 ENF-treated patients were analyzed monthly, from baseline to week 48.. There were 7 novel gp41 mutations positively associated with ENF treatment and correlated with classic ENF mutations. The ENF-associated clusters [V38A + N140I ] and [V 38A +T18A ] significantly correlated with an increase in CD4 cell count at week 48 ( an increase from baseline of 112 and 209 cells/microL, respectively), whereas [Q40H + L45M + 268A] significantly correlated with a decrease in CD4 cell count (-53 cells/microL), without a change in the level of viremia. Residues 38 and 18 are located complementarily to each other in the Rev-responsive element, whereas analysis of molecular dynamics showed that the copresence of [V38A + N140 I] abolishes the interaction between residue 38 and 145 important for stabilization of the 6-helix bundle. In contrast, T268A localizes in the gp41 calmodulin-binding domain responsible for gp41-induced CD4(+) T lymphocyte apoptosis.. Specific gp41 mutational clusters associated with ENF treatment significantly correlate with increases in CD4(+) cell count. Structural analysis suggests that this immunological gain is associated with mechanisms that act at both the protein level and the RNA level (even under conditions of virological failure). This result may help in the selection of patients who can benefit most from ENF treatment and represents a driving force for the design of the next generation of entry inhibitors.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Resistance, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Middle Aged; Models, Molecular; Mutation, Missense; Peptide Fragments; Viral Load; Viremia

Early virological response (VR) to enfuvirtide-based salvage regimens at week 12 has been described as a predictor of long-term therapeutic success. The relationship between enfuvirtide plasma exposure and VR has not yet been investigated in the clinical setting. Our aim was to investigate the role of enfuvirtide plasma exposure as a determinant of early VR in the clinical setting.. Forty-two multidrug-experienced patients starting a salvage enfuvirtide-based regimen were prospectively evaluated over a 12 week period. HIV-RNA levels and enfuvirtide C(trough) were regularly measured. VR was considered as achievement of viral load (VL) undetectability and/or a decrease of more than 1 log at week 12.. Optimized background score (OBS) and enfuvirtide C(trough) concentrations were associated with VL decrease at week 12. An OBS > or =2 and enfuvirtide C(trough) >2100 ng/mL were associated with VR. The pharmacokinetic/pharmacodynamic (PK/PD) analysis confirmed this exposure-response relationship both in the total population and in different groups according to OBS <2 or > or =2. Higher estimates of IC(50) were calculated for the OBS <2 group when compared with the OBS > or =2 group (7551 versus 2330 ng/mL, respectively), without a marked difference in I(0) (0.31 versus 0.21 log) and I(max) (-2.64 versus -3.33 log).. Enfuvirtide plasma exposure and OBS were found to significantly influence the magnitude and rate of early VR. The PK/PD modelling of enfuvirtide concentrations was different in our clinical setting, compared with previous data obtained under trial conditions. Therefore, optimization of enfuvirtide plasma exposure could deserve further evaluation as a determinant of therapeutic response in HIV-positive patients.

Topics: Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Inhibitory Concentration 50; Male; Middle Aged; Models, Statistical; Peptide Fragments; Plasma; Prospective Studies; Salvage Therapy; Treatment Outcome; Viral Load

Enfuvirtide (ENF), the first approved fusion inhibitor (FI) for HIV, is a 36-aa peptide that acts by binding to the heptad repeat 1 (HR1) region of gp41 and preventing the interaction of the HR1 and HR2 domains, which is required for virus-cell fusion. Treatment-acquired resistance to ENF highlights the need to create FI therapeutics with activity against ENF-resistant viruses and improved durability. Using rational design, we have made a series of oligomeric HR2 peptides with increased helical structure and with exceptionally high HR1/HR2 bundle stability. The engineered peptides are found to be as much as 3,600-fold more active than ENF against viruses that are resistant to the HR2 peptides ENF, T-1249, or T-651. Passaging experiments using one of these peptides could not generate virus with decreased sensitivity, even after >70 days in culture, suggesting superior durability as compared with ENF. In addition, the pharmacokinetic properties of the engineered peptides were improved up to 100-fold. The potent antiviral activity against resistant viruses, the difficulty in generating resistant virus, and the extended half-life in vivo make this class of fusion inhibitor peptide attractive for further development.

Topics: Amino Acid Sequence; Animals; Biophysical Phenomena; Biophysics; Drug Design; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Macaca fascicularis; Molecular Sequence Data; Peptide Fragments; Peptides; Protein Denaturation; Protein Folding; Protein Structure, Secondary; Temperature

Sequence variations in HR-1 gp41 env gene region encoding the target for T-20 have previously been reported among patients naive to inhibitory fusion.. To evaluate whether a previous therapeutic history of patients could have an impact on a differential evolution of the gp41 polymorphism.. We assessed the genetic polymorphism within the critical HR-1 gp41 env gene region in HIV-1 variants from 108 T-20-naive patients (Groups I-III) and 12 patients receiving T-20 as part of a salvage regimen (Group IV). T-20-naive patients included 50 patients exhibiting variants harboring resistance mutations to NRTIs, NNRTIs, and PIs (Group I), 24 patients with variants harboring resistance mutations for NRTIs and/or NNRTIs (Group II), and 34 antiretroviral drug-naive patients (Group III).. In T-20-naive patients whose HIV harbored resistance mutations to NRTIs, NNRTIs, and/or PIs, the mean number of synonymous mutations (ds) per patient was decreased and the mean number of nonsynonymous (da) mutations per patient was increased, resulting in a significant decrease in the mean Sigmads/Sigmada ratio as compared with antiretroviral drug-naive patients (Group III; 4.1 vs. 11.6; P < 0.0001). The mean number of polymorphic mutations in HR-1 gp41 per patient was two-fold higher in patients exhibiting antiretroviral drug resistance mutations (Groups I and II) than in antiretroviral drug-naive patients (Group III; 0.41 vs. 0.20; P < 0.05).. Our observations indicate that the HR-1 gp41 T-20 target is subjected to high genetic variability, including intrinsic polymorphism and selection of T-20 resistance mutations under T-20 intake, that is increased by the presence of resistance mutations to NRTIs, NNRTIs, and/or PIs. Our data provide a basis for a potential impact of previous antiretroviral drug history on the therapeutic efficacy of T-20.

Topics: Drug Resistance, Multiple; Drug Resistance, Viral; Enfuvirtide; Genes, pol; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Mutation; Peptide Fragments; Polymorphism, Genetic

In this study, we retrospectively assessed a gp41 genotypic assay in 404 enfuvirtide-naïve individuals (340 clade B, 64 non-B clade) to determine the prevalence of baseline polymorphisms and in 41 patients virologically failing enfuvirtide to determine correlates of resistance to this agent. Conserved and polymorphic regions of gp41 were identified in clade B isolates, with 127 of 328 codons (38.7%) being highly conserved (<1.0% variation) and 74 of 328 codons (22.6%) being partially conserved (1.0-5.0% variation). Polymorphisms were observed throughout gp41 in non-B clade virus sequences compared to the clade B reference strain, ranging from 53 natural substitutions in clade D to 76 in clade A. Insertions were common at positions 3, 105, 215 and 276. In the patients failing enfuvirtide, mutations were detected in the 10 amino acid region at positions 36-45 in all plasma virus sequences. Six additional mutations were selected outside of the common region which may be clinically significant at positions 33, 73, 75, 126, and 138. Two or three mutations at positions 36-45 were observed in the majority of plasma virus sequences from patients with virologic failure following the use of enfuvirtide. Further study is required to determine the clinical relevance of the clade related polymorphisms and the new mutations identified in the patients with virologic failure.

Topics: Adult; Amino Acid Sequence; Amino Acid Substitution; Base Pairing; Base Sequence; Canada; Codon; Drug Resistance, Viral; Enfuvirtide; Female; Genetic Variation; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Molecular Sequence Data; Mutagenesis, Insertional; Mutation; Peptide Fragments; Polymorphism, Genetic; Prevalence; Reproducibility of Results; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Sequence Analysis, DNA; Sequence Homology, Amino Acid

Data on susceptibility of HIV-1 non-B subtypes to Enfuvirtide (ENF) is rather limited.. To determine if ENF could be active in vitro against HIV-1 non-B subtypes and how the gp41 genetic variability across variants may influence ENF susceptibility.. Using PHENOSCRIPT Env, a recombinant envelope virus assay, ENF susceptibility was investigated in isolates from 19 drug-naive HIV-1-infected individuals harboring non-B subtypes.. Using phylogenetic analyses of the gp41 gene, distinct HIV-1 subtypes were recognized: A (2), C (5), D (1), F (2), G (1), J (1), CRF02_AG (6) and CRF06 (1). Susceptibility to ENF and IC(50) values in vitro could be obtained in only 13 (68.4%) specimens, most likely due to the high genetic variability in HR1 and HR2 regions in the remaining cases. A wide range of IC(50) values with a median of 0.013 microg/ml was observed (range, 0.005-0.180 microg/ml). Natural polymorphisms, but not classical ENF resistance associated mutations within HR1 (residues 36-45) were identified in most non-B viruses.. This study provides information about the baseline susceptibility to ENF in antiretroviral-naive subjects infected with different HIV-1 non-B subtypes. Susceptibility to ENF seems to be preserved despite high genetic variability in HR1 and HR2 regions.

Topics: Adult; Amino Acid Sequence; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Phylogeny

In most longitudinal clinical trials, some patients drop out before the end of the planned follow-up, and, in order to allow an all-patient intent-to-treat analysis to be performed, it is common practice to use some method of imputation to estimate values for missing data. However, different imputation methods may provide different results, and it is essential to investigate the sensitivity of the analysis using different imputation rules. In our analysis of two trials of the new HIV1 fusion inhibitor enfuvirtide, we compared some standard methods of imputing and analyzing HIV1-RNA data with two novel alternatives, to check the robustness of the primary endpoint results. The standard methods were: (1) last-observation-carried-forward, (2) baseline carried forward, and (3) multiple imputation. These were compared with a nearest-neighbour hot-deck method, specifically proposed for imputation of missing HIV1-RNA data, and with a heuristic approach: censored regression analysis of the last-observation-carried-forward. To supplement this analysis of real clinical trial data, we investigated the performance of the same imputation methods on simulated datasets designed to cover a broader range of missing data patterns.

Topics: Algorithms; Antiretroviral Therapy, Highly Active; Clinical Trials, Phase III as Topic; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Mathematical Computing; Models, Statistical; Patient Dropouts; Peptide Fragments; Research Design; RNA, Viral; Treatment Outcome

The clinical use of the human immunodeficiency virus (HIV) fusion inhibitor enfuvirtide (ENF) can select for drug-resistant HIV-1 strains bearing mutations in the HR1 region of the viral envelope (Env) protein. We analyzed the properties of multiple Env proteins isolated from five patients who experienced an initial decline in viral load after ENF therapy followed by subsequent rebound due to emergence of ENF-resistant HIV-1. Prior to ENF therapy, each patient harbored genetically and phenotypically diverse Env proteins that used CCR5 and/or CXCR4 to elicit membrane fusion. Coreceptor usage patterns of the Envs isolated from two patients underwent homogenization following ENF therapy, whereas in the other three patients, recombination appeared to allow the introduction of a single HR1 sequence with ENF resistance mutations into phenotypically distinct Env proteins. Analysis of individual Env clones also revealed that prior to ENF therapy, there was sometimes marked heterogeneity in the susceptibility of individual Env proteins to coreceptor inhibitors. After virologic failure, all Envs acquired resistance to ENF but exhibited no consistent change in their sensitivity to the fusion inhibitor T-1249 or to coreceptor inhibitors. In summary, using patient-derived Env proteins, we found that ENF failure was associated with emergence of high-level resistance to ENF due largely to mutations in HR1 but that susceptibility to other entry inhibitors was unaffected, that in these late-stage patients there was greater clonal variability to coreceptor than to fusion inhibitors, and that recombination events in vivo could sometimes restore Env genotypic and phenotypic heterogeneity by introducing drug-resistant gp41 sequences into heterologous gp120 backgrounds.

Topics: Anti-HIV Agents; Cell Line; Drug Resistance, Viral; Enfuvirtide; Gene Products, env; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Mutagenesis, Site-Directed; Mutation; Peptide Fragments; Phylogeny; Sensitivity and Specificity; Virus Internalization

Topics: Drug Resistance, Viral; Enfuvirtide; Genotype; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Mutation; Peptide Fragments; Polymorphism, Genetic

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Deoxycytidine; Emtricitabine; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Lopinavir; Male; Organophosphonates; Peptide Fragments; Pyrimidinones; Ritonavir; Tenofovir; Viral Load; Viremia

Topics: Darunavir; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; Humans; Peptide Fragments; Ritonavir; Sulfonamides

The human immunodeficiency virus type 1 (HIV-1) HR-1 and HR-2 gp41 regions were sequenced in a total of 228 plasma or peripheral blood mononuclear cell samples obtained from an equal number of enfuvirtide-naive subjects for pol genotypic resistance testing in clinical practice. Phylogenetic analysis of the env sequences indicated that 102 belonged to subtype B and 95 to non-B subtypes (31 CRF02_AG, 21 F1, 14 C, 11 A1/A2/A3, 9 CRF01_AE, 9 others) while the remaining 31 were unique recombinant forms. There was considerable variability in the consensus sequence of different clades, particularly in HR-2. The HR-1 amino acid region 36-45, containing all of the enfuvirtide resistance mutations so far characterized, was well conserved except for position 42 where serine and asparagine were unevenly distributed in different subtypes. Enfuvirtide resistance mutations were not present in any sample, reinforcing the expectation that enfuvirtide is effective against many different HIV-1 clades and recombinants. However, some of the mutations outside the amino acid 36-45 region and provisionally suggested to play a role in modulating resistance were detected in a minority of cases. Molecular epidemiological surveys coupled with long-term observation of in vivo response to enfuvirtide and future fusion inhibitors are required to clarify the clinical significance of gp41 natural variability.

Topics: Enfuvirtide; Genes, env; Genetic Variation; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Italy; Molecular Sequence Data; Peptide Fragments; Phylogeny

The EU approval of enfuvirtide (Fuzeon) was granted in May 2003 on the basis of the 48-week data from the TORO 1 and TORO 2 studies. Enfuvirtide is licensed for use in pretreated HIV patients experienced with three classes of drugs who exhibited treatment failure or who have shown intolerance to previous antiretroviral treatment regimens. Recent studies with the new protease inhibitors tipranavir and darunavir (RESIST and POWER studies) showed that a high proportion of heavily pretreated HIV patients achieve a viral load reduction to below the limit of detection when treated with enfuvirtide plus one of these new ritonavir-boosted protease inhibitors and an optimised background treatment regimen. The International AIDS Society (IAS-USA Panel) has recently updated its treatment guidelines in view of these new data and recommends the use of an antiretroviral treatment regimen containing at least two active drugs, one of which that has a new mechanism of action, for HIV patients who have been heavily pretreated. A new treatment goal has also emerged for heavily pretreated patients with advanced HIV disease: reduction of the viral load to below the detection limit of 50 copies/ml. The IAS concluded that the likelihood of achieving this treatment goal is higher when enfuvirtide is selected as one of the two active drugs.. A panel of German experts convened to discuss the currently available data and to incorporate them into the updated German consensus recommendations for the use of enfuvirtide when switching treatment in heavily pretreated HIV patients.. The consensus recommendations are based on published data from controlled, randomised clinical studies and on the expert opinions of the discussants.. The consensus recommendations were developed to provide practice-relevant standardised recommendations for selecting suitable candidates for enfuvirtide therapy and for their management. Aspects including predictive prognostic factors, disease stage, selection of the optimised background regimen, early indicators of a response to enfuvirtide, as well as accompanying educational measures treatment were considered. New protease inhibitors or other remaining active drugs should be used together with enfuvirtide in heavily pretreated patients in order to enable at least two active drugs to be included in such a salvage regimen.

Topics: Algorithms; Clinical Trials, Phase III as Topic; Drug Resistance, Viral; Enfuvirtide; Germany; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; Humans; Patient Education as Topic; Peptide Fragments; Randomized Controlled Trials as Topic; Treatment Outcome; Viral Load

Enfuvirtide (T-20) is the first approved HIV-1 entry into cells' inhibitor. It is a peptide with an amino acid sequence analogue to HR2 region of the viral surface glycoprotein gp41. Its mechanism of action is the competitive binding to HR1 region of the gp41, preventing the interaction between HR1 and HR2 and impeding the conformational changes in gp41 necessary for fusion of the virus with the cell. Its application is by subcutaneous injection. The main clinical trials of enfuvirtide (TORO 1 and 2) were performed in HIV-infected patients with virological failure, high antiretroviral experience and highly resistant viral isolates. Those trials showed that the addition of enfuvirtide to an optimized HAART (chosen with a resistance test) provided better results than HAART alone, measured by drop in viral load and immunologic benefit. The best results were observed in the subgroup of patients with more useful drugs in HAART (according to the information of the resistance test), a lower viral load, and a higher CD4 cell count at baseline. The most important adverse event is the production of injection drug hypersensitivity reaction in 98% of patients. The high cost is compensated by a reduction in costs derived from admissions.

Topics: Antiretroviral Therapy, Highly Active; CD4 Antigens; CD4 Lymphocyte Count; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; Treatment Failure; Viral Load

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cohort Studies; Cyclopropanes; Drug Information Services; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments; United States; United States Food and Drug Administration

Genotypic and phenotypic resistance in 11 HIV-1-infected patients receiving enfuvirtide (ENF), as part of a salvage regimen, has been evaluated.. Resistance mutations were detected by sequencing the gp41 ectodomain from plasma samples. During treatment, longitudinal samples from 1 patient were sequenced after limiting dilution of complementary DNA to isolate single genomes. Phenotypic resistance was evaluated with a new recombinant virus assay (PHENOSCRIPT; VIRalliance, Paris, France), allowing the determination of coreceptor use.. All patients experienced ENF failure. One to 4 mutations in the 36-to-45 gp41 region appeared during ENF therapy in all patients and disappeared after ENF removal. Mixtures of wild type and mutants unexpectedly persisted under ENF treatment, however, despite continued replication, leading to discordant results between genotypic and phenotypic data. Sequencing of isolated genomes from 1 patient confirmed that a wild-type first heptad repeat region (HR1) region was still present at the end of therapy. Several mutated variants coexisted at different time points, despite a tendency toward quasispecies reduction with time.. Individual variability of the mutation pattern and persistence of strains without mutation in the region mainly targeted by ENF resistance probably reflect the fact that resistance to ENF may rely on regions of gp41 or gp120 other than residues 36 to 45.

Topics: Amino Acid Sequence; Drug Resistance, Viral; Enfuvirtide; Genetic Variation; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation; Peptide Fragments; Phylogeny; Protein Structure, Tertiary; Retrospective Studies; Sequence Alignment; Treatment Failure; Viral Load

The treatment of patients with human immunodeficiency virus (HIV) infection and hemophilia involves unique challenges that may be addressed with novel antiretroviral classes. We describe the safety and efficacy of enfuvirtide therapy in 4 patients with severe hemophilia A. Although local skin reactions were common, neither local nor systemic bleeding worsened. Three patients achieved undetectable HIV loads with enfuvirtide salvage regimens.

Topics: Adult; Enfuvirtide; Hemophilia A; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Middle Aged; Peptide Fragments

Transmission of HIV-1 variants with resistance to reverse transcriptase (RT) and protease inhibitors has been widely characterized in developed countries. However, no clear evidence of primary resistance to HIV-1 fusion inhibitors has been shown so far. We wished to investigate the possibility of genotypic resistance to enfuvirtide (T20) in a cohort of antiretroviral-naive, recently infected patients.. We included patients from the Aquitaine Cohort with an estimated date of seroconversion in 2004 and 2005, a plasma sample obtained less than 18 months after seroconversion and no prior history of antiretroviral therapy. RT, protease and gp41 sequences were determined by direct population sequencing from plasma samples and drug resistance mutations were reported.. A total of 55 patients were included in the study. The overall prevalence of transmitted HIV-1 resistance was 20%. Two patients had viruses with resistance mutations to T20. The first case had an N42D mutation in the HR1 region of the gp41, along with transmitted resistance mutations in the protease (D30N, M361, N88D) and in the RT (M41L, L210W, T215D). The second case had a G36D HR1 mutation, with no evidence of other drug resistance mutations.. We have shown the first cases of primary resistance to T20 in recently infected patients in southwestern France. Epidemiological surveillance of the transmission of drug-resistant HIV-1 should include the resistance to T20.

Topics: Adult; Drug Resistance, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Male; Microbial Sensitivity Tests; Mutation; Peptide Fragments; Phylogeny

Resistance to the HIV fusion inhibitor enfuvirtide is associated with mutations in the first heptad repeat region of gp41, but little is known of their impact on replicative fitness in vivo. We followed seven patients undergoing salvage therapy that included enfuvirtide in order to document the temporal generation of genotypic and phenotypic resistance in parallel with replicative fitness. Resistance to enfuvirtide was not associated with decreased replicative fitness of HIV strains infecting these patients.

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Resistance, Viral; Enfuvirtide; Genotype; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Mutation; Peptide Fragments; Phenotype; Treatment Failure; Viral Load; Virus Replication

In RESIST, enfuvirtide co-administered with ritonavir-boosted tipranavir was associated with higher plasma tipranavir concentrations, which seldom rose above those associated with an increased risk of grade 3/4 transaminase elevations. Transaminase elevation rates (6.5%) and clinical hepatic event rates (5.9 events/100 person exposure years) were lower in the tipranavir/ritonavir with enfuvirtide group than in the tipranavir/ritonavir without enfuvirtide group. Observed increases in plasma tipranavir concentrations thus had no apparent effect on the risk of hepatotoxicity.

Topics: Alanine Transaminase; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Liver Diseases; Lopinavir; Peptide Fragments; Pyridines; Pyrimidinones; Pyrones; Randomized Controlled Trials as Topic; Ritonavir; Saquinavir; Sulfonamides; Treatment Outcome; Viral Load

Enfuvirtide is the only entry inhibitor approved for the treatment of human immunodeficiency virus (HIV)-1 infection. It is approved for use in adults and dosage recommendations exist for children aged 6 years or older.. T20-310 was a multicenter, open-label, nonrandomized, noncomparative study of the safety and efficacy of 2.0 mg/kg (maximum 90 mg) twice-daily subcutaneous enfuvirtide for 48 weeks in 52 treatment-experienced, HIV-1-infected pediatric patients (3-16 years) receiving optimized background therapy.. Enfuvirtide was generally well tolerated, and no new patterns of adverse events compared with adults were observed. Mild-to-moderate injection-site reactions were the most common adverse event. Of those participants on treatment for 48 weeks, the median change from baseline in HIV-1 RNA was -1.17 log10 copies/mL (n = 32), and there was a median CD4 change of +106 (n = 25) cells/mm3 and +4.7 CD4%. Seventeen (32.7%) patients achieved a viral load decrease of > or =1 log10 copies/mL and 11 (21.2%) achieved HIV-1 RNA <400 copies/mL. Virologic and immunologic treatment responses were substantially better for children (<11 years) than adolescents. Steady-state mean enfuvirtide C(trough) levels were stable during 24 weeks with no differences between children and adolescents.. Enfuvirtide is an effective treatment for HIV-1 infection in children and adolescents receiving optimized background therapy and has a favorable safety profile. Efficacy in adolescents was inferior; probably related to unique adherence challenges. The long-term safety and efficacy of enfuvirtide in pediatric patients is comparable to that observed in adults.

Topics: Adolescent; Anti-Retroviral Agents; Child; Child, Preschool; Enfuvirtide; Female; HIV Antibodies; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Multicenter Studies as Topic; Peptide Fragments; Treatment Outcome

To determine the severity of injection site reactions (ISRs), patient quality of life (QoL) and preference when enfuvirtide is administered by the Biojector (Bioject, Medical Technologies, Inc., Tualatin, OR, USA) relative to standard needles.. A total of 201 HIV-positive patients on stable enfuvirtide-based therapy (n=184) or initiating such therapy (n=17) were evaluated prospectively after switching from standard needles to the Biojector system. Patients used needles for a minimum of 2 weeks prior to switching to the Biojector. Questionnaires to assess the incidence and severity of ISRs (31-item score) and QoL [Medical Outcomes Study HIV Health Survey (MOS-HIV)] were administered at baseline and following a minimum of 14 days of Biojector use.. The median changes in ISR score and number of ISRs following a median of 1.0 month [interquartile range (IQR) 0.9, 1.3] of Biojector use were -3 (IQR -7, 1) and -1 (IQR -3, 1), respectively. The severity of pain (P<0.0001), induration (P<0.0001), pruritus (P<0.0001), nodules (P<0.0001) and erythema (P<0.0001) all decreased with the Biojector. Administration of enfuvirtide with the Biojector was associated with an improved patient QoL (P<0.0001), and was preferred by 72% of patients.. Compared with needles, the Biojector was associated with a decreased severity of ISRs and improved QoL in patients taking enfuvirtide.

Topics: Adult; Area Under Curve; Enfuvirtide; Female; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections; Male; Middle Aged; Patient Satisfaction; Peptide Fragments; Prospective Studies; Quality of Life; Self Care; Therapeutic Equivalency

Escalating drug resistance in treatment-experienced HIV-1-infected patients has made management increasingly difficult. In clinical trials, tipranavir (TPV) has produced potent and durable responses in such patients, although experience in clinical cohorts is limited. A retrospective clinical case review was undertaken of triple-class experienced HIV-1-infected patients receiving optimized boosted TPV-containing regimens and T20 with up to 108 weeks follow-up. Antiretroviral therapy (ART) resistance profiles were characterized using International Aids Society (IAS)-USA scoring and 'TPV resistance score' (TPV-RS) at baseline and failure. Five of 12 patients had undetectable virus (<50 copies/mL) after median 84 weeks (range 60-108), and 1/12 < had 700 copies/mL after 40 weeks. Six of 12 patients failed after 36 (range 12-48) weeks and were more likely to have > or = 3 TPV-RS mutations than non-failures (P = 0.06). Presence of a major IAS-USA mutation at baseline was strongly associated with absence of a 1 log viral load drop at 24 weeks (P = 0.02). TPV-containing regimens showed impressive efficacy and tolerability in this heavily experienced cohort.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; Genotype; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Middle Aged; Peptide Fragments; Pyridines; Pyrones; Retrospective Studies; Salvage Therapy; Sulfonamides; Treatment Outcome

To identify the prevalence and types of clinically significant drug interactions (CSDIs) in the drug regimens of patients with human immunodeficiency virus (HIV) infection who were receiving antiretroviral therapy, and to explore risk factors for these CSDIs.. Retrospective medical record review.. Academic HIV specialty clinic.. One hundred fifty-three randomly selected patients with HIV infection who were receiving antiretroviral therapy from May 1-September 30, 2006.. Data were collected on patient demographics, date of HIV diagnosis, most recent viral load and CD4(+) count, Centers for Disease Control and Prevention HIV classification, and comorbid conditions. Patients' drug regimens were analyzed for total and clinically significant antiretroviral drug interactions using three resources. Logistic regression and classification and regression tree analysis were used to identify independent CSDI predictors. Clinically significant drug interactions were defined as drug interactions that required a dosage adjustment or consisted of a drug combination that is contraindicated due to its high potential for clinical adverse effects. Of the 153 patients, at least one CSDI was found in 41.2% of their regimens: 34.6% with at least one drug interaction that required a dosage adjustment, 2.0% with at least one contraindicated drug combination, and 4.6% with at least one of each of these CSDIs. In the logistic regression model, risk factors independently associated with CSDIs were age older than 42 years (odds ratio [OR] 2.9, 95% CI 1.2-7.1), more than three comorbid conditions (OR 3.0, 95% CI 1.4-6.6), treatment with more than three antiretroviral agents (OR 2.4, 95% CI 1.0-5.8), and treatment with a protease inhibitor (OR 11.5, 95% CI 4.2-31.2). When directly compared, CSDIs were more prevalent among protease inhibitor-based than nonnucleoside reverse transcriptase inhibitor-based regimens (p<0.001).. Clinically significant drug interactions are highly prevalent among HIV-infected patients receiving antiretroviral therapy. Knowledge of the risk factors for CSDIs may help clinicians recognize and manage CSDIs.

Topics: Adult; Aged; Ambulatory Care Facilities; Antiretroviral Therapy, Highly Active; Community Health Centers; Drug Interactions; Drug Utilization Review; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; Humans; Logistic Models; Medical Records; Medical Records Systems, Computerized; Middle Aged; New York; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Prevalence; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk Factors

Genetic analysis of HIV-1 gp41 in plasma and peripheral blood mononuclear cell (PBMC) compartments was performed longitudinally in 10 HIV-infected patients treated with enfuvirtide. The appearance of enfuvirtide resistance mutations in PBMCs (DNA) generally occurred after (from 23 to 157 weeks) being recognizable in plasma (RNA). The disappearance of drug-resistant HIV-1 mutations to enfuvirtide in seven patients who discontinued the drug was directly dependent of the exposure time failing enfuvirtide, being associated mainly with the selection of secondary/compensatory mutations recognizable in proviral DNA.

Topics: Amino Acid Sequence; DNA, Viral; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Molecular Sequence Data; Mutation; Peptide Fragments; RNA, Viral; Salvage Therapy; Sequence Analysis, DNA; Treatment Failure

Enfuvirtide is the first of a new class of antiretroviral drugs that inhibits HIV entry. It is a 36 amino acid synthetic peptide that mimics the HR2 region of the HIV-1 gp41, preventing the fusion of viral and cellular membranes. Up to now, enfuvirtide was designed based on the HIV-1 B-subtype gp41, and resistance mutations to the fusion inhibitor have been investigated primarily in individuals infected with this subtype. To fill the gap, we analyzed the full length gp41 protein sequence of HIV-1 non-B strains from individuals receiving enfuvirtide-containing regimens. No primary resistance to the enfuvirtide binding domain (36-45 residues) was found. Resistance mutations were detected at follow-up visits and were comparable to those described among B-subtype HIV-1-infected patients; no sequence changes were detected in crucial HR1/HR2 gp41 sites such as the cytotoxic T lymphocyte epitope, cysteine loop, ectodomain, and 5-helix interaction and binding region.

Topics: Adult; Amino Acid Sequence; Drug Resistance, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Molecular Sequence Data; Mutation; Peptide Fragments; Phylogeny

The HIV fusion inhibitor enfuvirtide (ENF/Fuzeon) targets the env gp41 transmembrane domain. Mutations in gp41 are associated with ENF resistance. We developed a prototype assay to genotype a 676-bp region spanning the heptad repeat domains (HR1 and HR2) of HIV-1 gp41. Plasma samples were collected from 126 HIV-1-infected blood donors in Cameroon, Brazil, Uganda, South Africa, Thailand, and Argentina. Based on analysis of gag p24, pol integrase, and env gp41 genes, the panel was composed of subtypes A/A2 (18), B (11), C (14), D (10), F/F2 (9), G (7), CRF01_AE (9), CRF02_AG (33), and recombinant strains (15). Genotyping was successful for 119 of the 126 samples (94.4%). Although numerous amino acid polymorphisms were detected in some samples, none had primary mutations associated with ENF resistance. The gp41 HIV-1 research reagents developed by Celera are useful tools for genotyping analysis of the gp41 region in diverse HIV-1 strains.

Topics: Base Sequence; Drug Resistance, Viral; Enfuvirtide; Genotype; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Peptide Fragments; Polymorphism, Genetic; Protein Structure, Tertiary; Sequence Alignment

T-1249 is a peptide HIV fusion inhibitor (FI) previously under development for use in FI-naive and experienced patients. Here we present prospectively planned longitudinal analyses of FI resistance during 48 weeks of T-1249 dosing in patients with extensive prior FI exposure. T1249-105 was a single-arm rollover study in patients with prior resistance to enfuvirtide (ENF) and 10 days of T-1249 functional monotherapy exposure. The phenotype and genotype of plasma virus envelopes were analyzed at baseline and at study weeks 8, 16, and 48. At study entry, viruses had a geometric mean decrease in susceptibility to ENF of 51.8-fold but to T-1249 of 1.8-fold; extensive genotypic resistance to ENF was observed. A median viral load response of - 1.5 log(10) copies/ml was observed at week 2 that was partially sustained (- 0.5 log(10) copies/ml) through 48 weeks. Resistance to T-1249 gradually increased to a geometric mean 92.7-fold decrease from FI-naive baseline; this occurred concomitant with further evolution of gp41 amino acids 36-45, most commonly the G36D (n = 6, 16%) or N43K (n = 9, 24%) substitutions. A novel substitution, A50V (n = 12, 32%), was also common, as were the N126K and S138A substitutions in heptad-repeat 2 (HR-2). These data point toward a primary role for the gp41 36-45 locus in modulating FI binding and suggest that residues in HR-2 may contribute in a more limited manner to development of peptide FI resistance. These data also point toward a substantial genetic barrier and fitness cost to development of resistance to next-generation fusion inhibitors.

Topics: Amino Acid Substitution; Drug Resistance, Viral; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Longitudinal Studies; Microbial Sensitivity Tests; Peptide Fragments

An improved HPLC fluorimetric method for the quantification of enfuvirtide in plasma of HIV-infected subjects was described and validated. The use of an internal standard improved the reproducibility and precision of the analysis. Our method showed lower limits of detection and quantification (LOD = 32 ng/mL, LOQ = 78 ng/mL), lower intraday (RSD% 1.25-2.95) and interday (RSD% 1.75-4.69) coefficients of variation, greater recovery (>100%), lower duration (16 minutes) and lower cost than previously described fluorimetric methods. Therefore, this method can be used as a reliable tool for pharmacokinetic studies of enfuvirtide.

Topics: Chromatography, High Pressure Liquid; Drug Interactions; Enfuvirtide; Fluorometry; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments; Reproducibility of Results

Therapeutic drug monitoring (TDM) is gaining importance for improving the success of antiretroviral treatment in human immunodeficiency virus-infected patients. However, enfuvirtide (ENF) concentrations are not regularly determined. The objective of this work was to study the pharmacokinetics (PK) of ENF in patients treated in routine clinical settings, to develop a population PK model describing the concentration-time profile, and to establish PK reference values. A liquid chromatography-tandem mass spectrometry method was developed and applied to serum samples submitted for TDM. A two-compartment model with linear absorption and elimination was fitted to 329 concentrations from 131 patients. The PK model was used for simulations resulting in percentile curves for ENF levels for the full dosing interval. The model predicted that a median concentration of 1,968 ng/ml would be reached 12 h after administration of 90 mg of ENF, and 23% and 58% of patients are expected to have concentrations below 1,000 ng/ml and 2,200 ng/ml, respectively. Both values have been proposed as cutoffs for virological efficacy. The median maximum concentration of drug in serum (Cmax) of 3,943 ng/ml, predicted for 3 h after drug administration, is lower than the Cmax reported previously. We found an enormous interpatient variability at every time point, with concentration spectrums covering >1 log and 52% and 123% interindividual variabilities in the typical clearance and volume of distribution, respectively, in contrast to preexisting PK data. In summary, ENF levels are lower and more variable than expected. Many patients may achieve insufficient concentrations. Further covariate analysis in the population PK model might help to identify factors influencing the variability in ENF concentrations.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Middle Aged; Models, Biological; Peptide Fragments; Reference Values

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Middle Aged; Peptide Fragments; Treatment Outcome; Viral Load

Early virological response to antiretroviral therapy is predictive of long-term treatment outcome in therapy-naive patients. In treatment-experienced patients, such correlations are less well defined, because initial responses may be less pronounced and transient because of accumulated cross-resistance to prior therapies. Our objectives were to explore how the virological and immunological status of treatment-experienced patients at an early time point (week 12) during enfuvirtide-based therapy predicted their responses at weeks 24, 48, and 96 in the T-20 versus Optimized Regimen Only (TORO) trials.. Post hoc, modified, on-treatment and intent-to-treat analyses were performed to determine whether the relationship between virological and immunological outcomes at weeks 24, 48, and 96 were predicted by the patients' week-12 responses to therapy.. Using a modified on-treatment analysis for patients who, by week 12, achieved a decrease in their HIV-1 RNA load of > or =1 log10 copies/mL, 39.2% (95% CI, 33.6%-44.8%) and 59.5% (95% CI, 53.8%-65.1%) achieved a viral load of <50 copies/mL or <400 copies/mL at week 96, respectively, compared with 1.3% (95% CI, 0%-3.8%) and 2.6% (95% CI, 0%-6.1%) of patients, respectively, who did not achieve an early virological response. Using the same modified on-treatment analysis method for patients who, at week 12, achieved a CD4 cell count increase of > or =50 cells/mm3, 87.2% (95% CI, 82.6-91.8) maintained or improved this response through week 96, compared with 56.6% (95% CI, 47.5-65.8) of patients who did not achieve this early categorical immunological response.. Enfuvirtide-based treatment regimens are associated with a rapid and durable response. Week-12 virological and immunological responses to treatment with enfuvirtide are predictive of subsequent outcomes in triple-class treatment-experienced patients.

Topics: Clinical Trials, Phase III as Topic; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; Randomized Controlled Trials as Topic; Regression Analysis; Time Factors; Treatment Outcome; Viral Load

Topics: Animals; Antiviral Agents; CCR5 Receptor Antagonists; Cell Adhesion; Drug Design; Enfuvirtide; HIV; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Membrane Fusion; Peptide Fragments; Piperazines

The use of previously successful antiretroviral regimens in mother-to-child transmission (MTCT) prevention will be increasingly challenged by the rising prevalence of multidrug-resistant (MDR) HIV. We used enfurvitide together with an optimized antiretroviral backbone to prevent the MTCT prevention of MDR HIV in two pregnant women. The measurement of maternal and foetal peripheral blood levels of enfurvitide showed no evidence of transplacental transfer.

Topics: Adult; Drug Resistance, Multiple, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Maternal-Fetal Exchange; Peptide Fragments; Pregnancy; Pregnancy Complications, Infectious

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections, Jet; Joints; Male; Peptide Fragments; Peripheral Nervous System Diseases

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.

Topics: CD4 Lymphocyte Count; Computer Simulation; Cost-Benefit Analysis; Disease Progression; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Markov Chains; Models, Biological; Peptide Fragments; Quality of Life; Survival Analysis; Treatment Failure; Treatment Outcome; United States

We previously reported that enfuvirtide (ENF) treatment is accompanied by a selective increase of serum IgE. We asked whether ENF had intrinsic capability to direct B-lymphocytes to switch to IgE and/or if it could drive CD4 T cells to a Th2 phenotype. ENF was added in vitro: (a) to B-lymphocytes stimulated with IgE-switch inducing stimuli; (b) to peripheral blood mononuclear cells. Total IgE production by B cells and IL4 and IFN-gamma production by CD4 T lymphocytes were evaluated, respectively. ENF had no measurable effect on the IgE production by B-lymphocytes. In contrast, it sharply increased the IL4 to IFN-gamma (a correlate of the Th2 phenotype) when added in vitro to T cells from healthy donors or from single ENF-treated patients. The hyper-IgE production in ENF-treated patients is associated with the in vitro induction of a type-2 phenotype in CD4 T cells.

Topics: Anti-HIV Agents; B-Lymphocytes; CD4-Positive T-Lymphocytes; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Immunoglobulin Class Switching; Immunoglobulin E; Peptide Fragments; Th2 Cells

Topics: Adult; Antiretroviral Therapy, Highly Active; Drug Resistance, Multiple, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Peptide Fragments; Pregnancy; Pregnancy Complications, Infectious; Pyridines; Pyrones; Sulfonamides

Topics: Biomedical Research; Enfuvirtide; History, 20th Century; History, 21st Century; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments; Research Support as Topic; United States

Treatment options for HIV-1 infected individuals who have received extensive previous antiretroviral therapy are limited. We compared efficacy and safety of the novel non-peptidic protease inhibitor tipranavir co-administered with ritonavir plus an optimised background regimen with that of an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI-ritonavir) in such patients.. We did a combined analysis of 48-week data from two ongoing, randomised, open-label, multinational, phase III, RESIST studies. HIV-1-infected adults with 3 months or longer previous triple antiretroviral class experience, two or more previous protease inhibitor regimens, HIV-1 RNA 1000 copies per mL or greater, and genotypically demonstrated primary resistance to protease inhibitor, were eligible. Primary endpoints were proportion of treatment responders (with reduction in viral load of 1 log(10) copies per mL or greater below baseline without treatment change) at 48 weeks and time to treatment failure through 48 weeks (intention-to-treat analysis). The RESIST studies are registered with ClinicalTrials.gov, numbers NCT00054717 (RESIST-1) and NCT00144170 (RESIST-2).. 3324 patients were screened; 746 received tipranavir-ritonavir and 737 CPI-ritonavir. 486 (65.1%) patients on tipranavir-ritonavir and 192 (26.1%) on CPI-ritonavir remained on assigned treatment until week 48. At week 48, more patients achieved and maintained treatment response in the tipranavir-ritonavir group than in the CPI-ritonavir group (251 [33.6%] vs 113 [15.3%]; p<0.0001). Median time to treatment failure was significantly longer in the tipranavir-ritonavir group than in the CPI-ritonavir group (113 days vs 0 days; p<0.0001). Gastrointestinal system disorders and raised transaminase, cholesterol, and triglycerides were more frequent in the tipranavir-ritonavir group than in the CPI-ritonavir group.. Compared with CPI-ritonavir, tipranavir-ritonavir with an optimised background regimen provides better virological and immunological responses over 48 weeks in patients who have received extensive previous antiretroviral treatment.

Topics: Adult; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Logistic Models; Male; Multicenter Studies as Topic; Peptide Fragments; Pyridines; Pyrones; Randomized Controlled Trials as Topic; Ritonavir; Sulfonamides; Time Factors; Treatment Failure; Viral Load

To investigate gp41 variability and correlation with viro-immunological parameters in 54 HIV-1-infected patients receiving enfuvirtide added as single active drug to a failing regimen.. One hundred and two HIV-1 gp41 sequences and clinical follow-up from 54 enfuvirtide-treated patients were analysed from baseline to week 36 of treatment. The association of mutations with viraemia/CD4 count was assessed by Mann-Whitney test.. The addition of enfuvirtide to the failing regimen induced at week 4 a viraemia decrease from 5.1 to 4.3 log(10)/mL (P = 0.0002) and a CD4 increase from 48 to 106 cells/mm(3) (P = 0.008). While viraemia rebounded to 4.8 and 4.6 log(10)/mL at week 12 and 36, respectively, CD4 continued to increase to 136 cells/mm(3) at week 36. Enfuvirtide resistance mutations, rarely found at baseline, occurred in 45/54 (83.3%) enfuvirtide-treated patients. V38A/E were the most represented mutations at all time-points. The presence of V38A/E was significantly associated with a 4.5-fold CD4 increase from baseline to week 24 and with a 6-fold increase at week 36 (P = 0.004 and 0.02 compared without V38A/E, respectively), without significant correlation with viraemia. In contrast, Q40H + L45M (present in six enfuvirtide-treated patients at week 36) correlated with CD4 loss from baseline to week 36 (P = 0.02), without significant correlation with viraemia. Mutation N126K (observed in six enfuvirtide-treated patients, never found at baseline) abrogates the fourth gp41 glycosylation site and correlates with a 2.1-fold CD4 increase at week 24.. Specific enfuvirtide resistance mutations (V38A/E) are associated with a sustained CD4 increase, without remarkable effects upon viraemia. This CD4 recovery, due to virus- and immune-mediated mechanisms most probably not applicable to protease/reverse transcriptase inhibitors, is important for innovative therapeutic strategies.

Topics: Adult; CD4 Lymphocyte Count; Drug Resistance, Viral; Enfuvirtide; Female; Glycosylation; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Mutation; Peptide Fragments; Polymerase Chain Reaction; Sequence Analysis, DNA; Treatment Outcome; Viremia

The aim of the study was to evaluate, under routine circumstances, the immunological and virological efficacy of antiretroviral regimens containing enfuvirtide in multi-class experienced HIV-1 infected patients. This retrospective monocentric study analyzed the clinical, immunological, and virological data of 18 HIV-1 infected patients who started enfuvirtide and completed at least 3 months of therapy. Following 3 months of enfuvirtide therapy, 11 (61%) patients had HIV-1 RNA below 400 copies/ml, among whom 8 (44%) patients below 50 copies/ml. In the ten patients still receiving enfuvirtide after 12 months, the median increase in CD4 cell count was 159 cells/microl (range, -25 to +301) and the mean decrease in HIV-1 RNA was 2.5 +/- 1.4 log(10) copies/ml; in six of these patients, viral load remained below 50 copies/ml. Five patients discontinued enfuvirtide for virological failure but none as a consequence of adverse event. Mutations located within the 36-45 amino acid domain of HR1 region of gp41 and associated to enfuvirtide resistance were found in all seven patients with persistent viral replication. In addition, a new mutation, A50V, emerged in one patient with late viral rebound. Its disappearance after treatment discontinuation suggests that it could play a role in resistance to enfuvirtide. In conclusion, enfuvirtide may be a good therapeutic option as rescue therapy in treatment-experienced patients. However, the mutations conferring resistance to enfuvirtide develop rapidly when viral load is not controlled confirming that enfuvirtide should be prescribed in association with an active background regimen.

Topics: Adult; Aged; CD4 Lymphocyte Count; Cohort Studies; Drug Resistance, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Hospitals, Teaching; Humans; Male; Middle Aged; Mutation; Peptide Fragments; Protein Structure, Tertiary; Retrospective Studies; RNA, Viral; Salvage Therapy; Treatment Outcome; Viral Load

The performance of a gp41 assay, created using reagents designed for use with the OpenGene DNA Sequencing System, was evaluated using a panel of plasma samples obtained from enfuvirtide-naive and -experienced human immunodeficiency virus type 1-infected subjects. Resulting sequence data were highly accurate compared to a "home brew" assay and clonal sequence analysis.

Topics: Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Microbial Sensitivity Tests; Mutation; Peptide Fragments; Sequence Analysis, DNA

Investigate the metabolic and mitochondrial effects of switching a highly active antiretroviral therapy (HAART) regimen with a high mitochondrial toxicity profile to a HAART with a theoretically low mitochondrial toxicity.. Six consecutive HAART-experienced patients receiving at least one dideoxy-nucleoside reverse transcriptase inhibitor (NRTI) switched to enfuvirtide plus tenofovir plus saquinavir/ritonavir (T20+TDF+SQV/r). Blood samples were collected at baseline, 12 and 24 weeks after the switch, and viral load (VL) and lymphocyte CD4+ T-cell count were determined. Metabolic parameters consisted of fasting serum triglycerides, cholesterol (total and fractions), glucose, insulin, C-peptide and lactate. Mitochondrial assessment consisted on mitochondrial DNA (mtDNA) quantification, COX-II mitochondrial protein expression rate, mitochondrial respiratory chain complex III and IV activities, and oxygen consumption in peripheral blood mononuclear cells. For baseline mitochondrial comparisons, we included six HIV-infected patients naive for ART.. Switched patients exhibited a mean increase of 26 CD4+ T-cells/mm3 and a mean decrease of 1.1 log in VL (P = NS for both). Lactate, lipids and glycaemia remained stable during the study; only insulin levels increased significantly (P < 0.05). Switched patients exhibited, at baseline, low mitochondrial measurements, being significant only for complex III and IV activities with respect to naive patients (P < 0.05 for both). MtDNA content did not rise significantly during the study. However, we observed increases in COX-II mitochondrial protein synthesis (124%, P < 0.05), complex III activity (127%, P < 0.05), complex IV activity (86%, P = 0.37) and oxygen consumption (194%, P < 0.05).. Switching a HAART-containing dideoxy-NRTI to T20+TDF+SQV/r minimally alters metabolic parameters and exerts beneficial effects on mitochondrial function at 24 weeks. Mitochondrial improvement should be considered as an additional advantage of this rescue therapy.

Topics: Adenine; Adult; Aged; Antiretroviral Therapy, Highly Active; DNA, Mitochondrial; Electron Transport Complex III; Electron Transport Complex IV; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; Humans; Insulin; Leukocytes, Mononuclear; Male; Middle Aged; Mitochondria; Organophosphonates; Oxygen Consumption; Peptide Fragments; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Tenofovir

Darunavir (Prezista--Tibotec), a new protease inhibitor, has received accelerated approval from the FDA for use in combination therapy of human-immunodeficiency-virus (HIV) infection in previously treated adults. It is coadministered with low-dose ritonavir (Norvir), which increases its bioavailability.

Topics: Antiretroviral Therapy, Highly Active; Biological Availability; Blood Proteins; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Darunavir; Drug Approval; Drug Interactions; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Peptide Fragments; Protein Binding; Randomized Controlled Trials as Topic; Ritonavir; RNA, Viral; Sulfonamides; Tablets; Time Factors; United States; Viral Load

Fifty-five patients placed on tipranavir/ritonavir 500/200 mg twice a day (27 with enfuvirtide and 28 without) underwent tipranavir and ritonavir plasma concentration measurements by high-pressure liquid chromatography. Markedly higher tipranavir and ritonavir trough concentrations were observed in enfuvirtide recipients. The modelling of sparse plasma samples using a first order absorption and elimination monocompartmental model without time lag predicted higher tipranavir elimination half-life and volume of distribution in enfuvirtide takers. This unexpected drug-drug interaction warrants further investigation.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cohort Studies; Drug Interactions; Enfuvirtide; Female; Half-Life; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Peptide Fragments; Pyridines; Pyrones; Ritonavir; Sulfonamides

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.

Topics: Drug Eruptions; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections, Subcutaneous; Patient Compliance; Peptide Fragments; Self Administration

To analyse the genetic changes in the gp41 protein in HIV-infected patients with detectable plasma viraemia receiving a long-term salvage enfuvirtide regimen.. We studied 13 heavily antiretroviral-experienced patients receiving a salvage regimen containing enfuvirtide. Substitutions in gp41 were analysed by population-based sequencing at baseline and longitudinally after the initiation of enfuvirtide treatment. To investigate sequence evolution we also analysed multiple gp41 clones from four selected patients. A Fisher's two-tailed test was used to assess the distribution of resistance-associated mutations in the clonal sequences.. Mutations at positions 36 and 38 in gp41 (HR1) emerged rapidly (median emerging time 10 weeks), but disappeared at subsequent timepoints in most of the patients. Amino acid changes did not accumulate over time, with no patient having more than two mutations in HR1 after 6 months of treatment. The mutation N43D was not observed together with changes at positions 36 or 38 in any patient. Clonal analysis showed that the three main gp41 resistance mutations were highly mutually exclusive (P < 0.001), being present in individual clones and constituting independent populations.. Substitutions at positions 36 and 38 are rapidly selected but disappear thereafter in HIV-1-infected patients failing an enfuvirtide-containing salvage therapy. We found a highly exclusive relationship between the three main enfuvirtide resistance-associated mutations (amino acids 36, 38 and 43), suggesting that the genetic evolution of HIV-1 gp41 protein is a dynamic and much more complex process than previously though.

Topics: Amino Acid Sequence; Drug Resistance, Viral; Enfuvirtide; Evolution, Molecular; Follow-Up Studies; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Mutation; Peptide Fragments; Salvage Therapy; Treatment Failure; Viremia

Topics: Adult; Antiretroviral Therapy, Highly Active; Desensitization, Immunologic; Drug Eruptions; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments

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

Topics: Adult; CD4 Lymphocyte Count; Drug Resistance, Multiple, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Immunoglobulin E; Male; Middle Aged; Peptide Fragments

Careful examination of viral dynamics during antiretroviral treatment can provide important insights into HIV pathogenesis. We examined viral evolution during and after enfuvirtide (T-20) treatment with an objective of defining the characteristics of viral evolution during advanced HIV immunodeficiency. Specifically, we examined the viral quasispecies from nine patients who experienced incomplete viral suppression on an enfuvirtide-based regimen, and who subsequently interrupted enfuvirtide while remaining on a stable optimized background regimen (enfuvirtide "partial treatment interruption"). On average, eight clones were sequenced from three time points: pre-enfuvirtide, post-enfuvirtide failure, and post-enfuvirtide interruption. We utilized a Bayesian hierarchical phylogenetic model to assess the evolutionary relatedness of the virus that emerged over time. In most subjects, interruption of enfuvirtide was associated with continued viral evolution as enfuvirtide mutations waned; in no subject did we find clear evidence supporting the reemergence of archived wild-type variants (Bayes factor=30.2, p=0.01). Evidence supporting ongoing viral evolution was particularly strong in subjects whose virus remained diverse or became more diverse during enfuvirtide therapy. In contrast to observations when all drugs are interrupted, loss of resistance during enfuvirtide interruption is most likely due to ongoing viral evolution (and back-mutation), rather than emergence of an archived virus.

Topics: Bayes Theorem; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Enfuvirtide; Evolution, Molecular; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Peptide Fragments; Phylogeny; Virus Replication

Topics: Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Organic Chemicals; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; Viral Load

The relationship between sensitivity to antiviral drugs and viral fitness is of paramount importance in understanding the long-term implications of clinical resistance. Here we report the development of a novel recombinant virus assay to study entry inhibitor-resistant HIV variants using a biologically relevant cell type, primary CD4 T-cells. We have modified the replication-competent molecular clone HIV(NL4-3) to express a reporter protein (Renilla luciferase), Green Fluorescent Protein (EGFP), or Red Fluorescent Protein (DsRed2) upon infection, thus allowing quantification of replication. Luciferase-expressing virus was used to evaluate drug sensitivity, while co-infection with viruses carrying the green and red fluorescent proteins was employed in the competitive fitness assay. Using envelope proteins from three T20 insensitive variants, lower levels of resistance were observed in primary CD4 T-cells than had been previously reported for cell lines. Importantly, dual-color competition assays demonstrated comparable or higher fitness for these variants despite their reduced T20 sensitivity. We conclude that reduced sensitivity to T20 is compatible with high viral fitness in the absence of selection pressure. Thus, simultaneously measuring both resistance and viral fitness using this newly described dual-color competition assay will likely provide important information about resistant viral variants that emerge during therapy with entry inhibitors.

Topics: Amino Acid Sequence; CD4-Positive T-Lymphocytes; Cell Line; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Kinetics; Microbial Sensitivity Tests; Molecular Sequence Data; Peptide Fragments; Sequence Homology, Amino Acid; Virus Replication

The natural occurrence of primary resistance mutations in reverse transcriptase (RT) and protease (PR) genes of HIV-1 isolates from untreated patients has been reported and it may have important implications for the response to drug treatment. It is predictable that the same occurs in the HR1 region of gp41 sequence from patients who have never received T20 therapy, and in this regard it would be important to know not only the mutation frequencies at HR1 region but also the natural polymorphisms at resistance-associated positions present in the absence of this drug.. The objectives of this study are to investigate the existence of natural resistance-associated mutations to T20 in HR1 gp41 region corresponding to different HIV-1 genetic forms from T20 naive patients and to determine their prevalence.. Two hundred HIV-1 gp41 sequences were included: subtype B: 164 (81.3%); subtype A: 15 (8.2%); subtype G: 10 (4.6%); subtype F: 6 (3.5%); subtype C: 3 (1.8%); subtype K: 1 (0.6%); and subtype D: 1 (0.6%). We analyzed the resistance-associated mutations previously described: Q32H/R, G36D/S, I37V, V38A/M, Q39R/H, Q40H, N42T/D/Q/H, N43D/S/K/Q, L44M, L45M, R46M and V69I.. Natural resistance mutations to T20 were found at a high frequency: 10.5%, corresponding to 9.1% in subtype B and 16.7% in non-B subtype samples. Polymorphisms were more frequent in non-B and recombinant forms than in subtype B (p<0.001). Different substitutions were related to subtypes: N42S in subtypes A, B, G and C, but not in F, Q56R in subtype A from CRF02_AG, and L54M in subtype B from CRF14_BG.. To our knowledge this is the first study describing natural-resistance to T20 among different HIV-1 subtypes, warranting a study of the biological significance of this mutations and their clinical relevance. The detection of differences between subtypes may have an influence on the rate and patterns of resistance in patients undergoing T20 treatment.

Topics: Amino Acid Sequence; Anti-HIV Agents; DNA, Complementary; DNA, Viral; Drug Resistance, Viral; Enfuvirtide; Gene Frequency; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation; Peptide Fragments; Polymorphism, Genetic; RNA, Viral; Sequence Alignment; Sequence Analysis, DNA; Spain

The anti-HIV drug T20 is a synthetic peptide derived from the HR2 region of HIV-1 gp41. T20 contains the sequence ELDKWA, which binds the broadly neutralizing antibody 2F5. Using plates coated with T20 or with synthetic peptides and recombinant proteins representing gp120 or gp41 domains, this study investigated by enzyme-linked immunosorbent assay the levels of antibodies directed to the gp160 molecule in patients treated with T20. Analysis of sera obtained before and after administration of T20 indicated that the levels of antibodies directed to T20, to MBP44, a maltose binding protein representing the HR2 region, and to 4765, a synthetic peptide containing the sequence ELDKWA, fell following administration of T20, while the levels of antibodies directed to other regions of gp41 ectodomain and to gp120 remained stable. The decline observed was independent of the viral load and of the total IgG concentration. Follow-up studies with sera obtained from HIV-1-seropositive patients naive to T20 indicated no decline in the level of antibodies directed to HR2 and other regions of gp160. Analysis of sera obtained from a patient after 2 months of T20 treatment interruption showed a level of antibodies to the HR2 region similar to that measured before administration of T20. The addition of increasing amounts of T20 to sera from T20-naive patients decreased the level of serum antibodies against peptide 4765, T20, and MBP44. The observation of antibody depletion by T20 suggests that anti-gp41 antibodies may interfere with T20 treatment by forming T20-antibody complexes.

Topics: Adult; Amino Acid Sequence; Antigen-Antibody Complex; Antiretroviral Therapy, Highly Active; Carrier Proteins; Enfuvirtide; Enzyme-Linked Immunosorbent Assay; Female; HIV Antibodies; HIV Antigens; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; Humans; Immunoglobulin G; Male; Maltose-Binding Proteins; Middle Aged; Molecular Sequence Data; Oligopeptides; Peptide Fragments; Viral Load

Topics: Adult; Desensitization, Immunologic; Drug Eruptions; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments

Enfuvirtide (ENF/T-20/Fuzeon), the first human immunodeficiency virus (HIV) entry inhibitor to be licensed, targets a structural intermediate of the entry process. ENF binds the HR1 domain in gp41 after Env has bound CD4, preventing conformational changes needed for membrane fusion. Mutations in HR1 that confer ENF resistance can arise following ENF therapy. ENF resistance mutations were introduced into an R5- and X4-tropic Env to examine their impact on fusion, infection, and sensitivity to different classes of entry inhibitors and neutralizing antibodies. HR1 mutations could reduce infection and fusion efficiency and also delay fusion kinetics, likely accounting for their negative impact on viral fitness. HR1 mutations had minimal effect on virus sensitivity to other classes of entry inhibitors, including those targeting CD4 binding (BMS-806 and a CD4-specific monoclonal antibody [MAb]), coreceptor binding (CXCR4 inhibitor AMD3100 and CCR5 inhibitor TAK-779), or fusion (T-1249), indicating that ENF-resistant viruses can remain sensitive to other entry inhibitors in vivo. Some HR1 mutations conferred increased sensitivity to a subset of neutralizing MAbs that likely target fusion intermediates or with epitopes preferentially exposed following receptor interactions (17b, 48D, 2F5, 4E10, and IgGb12), as well as sera from some HIV-positive individuals. Mechanistically, enhanced neutralization correlated with reduced fusion kinetics, indicating that, in addition to steric constraints, kinetics may also limit virus neutralization by some antibodies. Therefore, escape from ENF comes at a cost to viral fitness and may confer enhanced sensitivity to humoral immunity due to prolonged exposure of epitopes that are not readily accessible in the native Env trimer. Resistance to other entry inhibitors was not observed.

Topics: CD8-Positive T-Lymphocytes; Drug Resistance, Viral; Enfuvirtide; Gene Products, env; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Mutation; Neutralization Tests; Peptide Fragments

Topics: Adolescent; Child; Child, Preschool; Clinical Trials as Topic; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Peptide Fragments

Topics: Adult; Drug Resistance, Multiple, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Peptide Fragments; Pregnancy; Pregnancy Complications, Infectious

Topics: Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; Clinical Trials as Topic; Drug Administration Schedule; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Long-Term Care; Male; Peptide Fragments; Prognosis; Risk Assessment; Survival Analysis; Viral Load; Virus Replication

A method for measuring a human immunodeficiency virus (HIV) cell membrane fusion inhibitor (T-20/Ro 29-9800) and its metabolite (M-20/Ro 50-6343) in human plasma by liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed. The relatively large peptide analytes and their corresponding deuterated (d(10)) peptides used as internal standard were isolated from plasma by protein precipitation with two volumes of acetonitrile to plasma. A large pore size reversed-phase C(18) column was employed to elute the peptides. A triple quadrupole mass spectrometer with electrospray interface operating in positive ion and multiple reaction monitoring modes with transitions m/z 1124-->1343 for both T-20 and M-20 was utilized for peak detection. The advantages of the method were a simple sample preparation, specific and sensitive MS/MS detection, and a wide dynamic range of 10-2000 ng/ml for T-20. The method was validated and used for analyzing samples from clinical studies to provide pharmacokinetic profiles of the HIV fusion inhibitor peptide drug and its metabolite.

Topics: Adsorption; Amino Acid Sequence; Calibration; Chromatography, Liquid; Drug Stability; Drugs, Investigational; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Mass Spectrometry; Molecular Sequence Data; Peptide Fragments; Reference Standards; Reproducibility of Results; Technology, Pharmaceutical

A preliminary open-label study on the administration of the novel, parenteral HIV fusion inhibitor enfuvirtide as a part of a salvage antiretroviral treatment in a cohort of hardly pretreated and multiresistant patients with advanced HIV disease followed until 30 consecutive months of therapy is presented, and discussed on the ground of available experiences, and an update of literature evidences in this field. Expectations and concerns on the use of this novel anti-HIV compound (belonging to an innovative pharmacological class) in daily practice are debated, since no specific recommendations have been produced until now, and enfuvirtide administration appears significantly more effective when made in conjunction with at least one or two other active antiretroviral agents. The management of the very frequent site injection reactions represents an adjunctive problem in the treatment of these multi-problematic patients.

Topics: Adolescent; Adult; Disease Progression; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Middle Aged; Peptide Fragments

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.

Topics: Amino Acid Sequence; Cameroon; Conserved Sequence; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Peptide Fragments; Recombination, Genetic; Sequence Analysis, DNA

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

Our objective was to characterize population pharmacokinetics of enfuvirtide, 90 mg twice daily injected subcutaneously, in treatment-experienced human immunodeficiency virus type 1 (HIV-1)-infected patients, as well as the relationship between exposure and antiviral effect.. Plasma concentrations of enfuvirtide and HIV-1 ribonucleic acid were obtained from 628 patients in 2 phase III studies. NONMEM software was used for population pharmacokinetic analysis and to assess the effects of age, gender, body weight, anti-gp41 antibodies, and concomitant drugs. Enfuvirtide exposure (area under the plasma concentration-12-hour time curve or steady-state trough concentration) was calculated from individual parameter estimates derived from the model. The decline in HIV-1 ribonucleic acid from baseline at week 2 or 24 was regressed against estimates of enfuvirtide exposure by a maximum effect model. The exposure-response relationship was examined in functional monotherapy (phenotypic sensitivity score of 0) and combination therapy (phenotypic sensitivity score > or = 1).. Enfuvirtide population pharmacokinetics was well described by a 1-compartment model with first-order absorption and elimination. Body weight and female gender were identified as affecting apparent clearance but not efficacy and safety. Concomitant medications had no significant effect on enfuvirtide pharmacokinetics. Antiviral response to enfuvirtide was independent of drug exposure, suggesting that the approved 90-mg twice-daily dose was in the plateau portion of the dose-response curve. For functional monotherapy (phenotypic sensitivity score of 0), approximately 66% of estimated maximal effect was achieved at week 2 and 73% at week 24, and for combination therapy, more than 92% was achieved at both weeks 2 and 24.. Body weight and gender affected enfuvirtide clearance, but changes in exposure did not affect efficacy or safety. Efficacy reached a plateau at the 90-mg twice-daily dosage in the exposure-response curve.

Topics: Adult; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Treatment Outcome; Viral Load

A high diversity within the HR1/HR2 regions of viral gp41 and one natural change (N42D) within the 36-45 aa domain in HIV-1 group O in comparison with HIV-1 group M isolates have led us to suspect that enfuvirtide (ENF) should not be active against HIV-1 group O. We analyzed in vitro and in vivo the antiviral activity of ENF against HIV-1 group O isolates. The IC50 at baseline was 0.15 +/- 0.028 microg/ml in a clinically derived virus specimen. After initiating treatment with ENF, a significant decline in plasma HIV-RNA and CD4 gain was noticed in one patient. Therefore, individuals with HIV-1 group O strains might benefit from ENF therapy.

Topics: Adult; Amino Acid Sequence; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Peptide Fragments; Sequence Analysis, DNA; Treatment Outcome

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; Enfuvirtide; Enzyme Inhibitors; Histone Deacetylase 1; Histone Deacetylase Inhibitors; HIV; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Valproic Acid; Virus Latency

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.

Topics: Anti-HIV Agents; Cell Fusion; Circular Dichroism; Cysteine; Disulfides; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Inhibitory Concentration 50; Membrane Fusion; Neutralization Tests; Peptide Fragments; Protein Denaturation; Protein Structure, Quaternary; Recombinant Fusion Proteins; Structure-Activity Relationship; Temperature; Thermodynamics

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.

Topics: Drug Design; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Molecular Structure; Peptide Fragments

Enfuvirtide (ENF), a novel human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, has potent antiviral activity against HIV-1 both in vitro and in vivo. Resistance to ENF observed after in vitro passaging was associated with changes in a three-amino-acid (aa) motif, GIV, at positions 36 to 38 of gp41. Patients with ongoing viral replication while receiving ENF during clinical trials acquired substitutions within gp41 aa 36 to 45 in the first heptad repeat (HR-1) of gp41 in both population-based plasma virus sequences and proviral DNA sequences from isolates showing reduced susceptibilities to ENF. To investigate their impact on ENF susceptibility, substitutions were introduced into a modified pNL4-3 strain by site-directed mutagenesis, and the susceptibilities of mutant viruses and patient-derived isolates to ENF were tested. In general, susceptibility decreases for single substitutions were lower than those for double substitutions, and the levels of ENF resistance seen for clinical isolates were higher than those observed for the site-directed mutant viruses. The mechanism of ENF resistance was explored for a subset of the substitutions by expressing them in the context of a maltose binding protein chimera containing a portion of the gp41 ectodomain and measuring their binding affinity to fluorescein-labeled ENF. Changes in binding affinity for the mutant gp41 fusion proteins correlated with the ENF susceptibilities of viruses containing the same substitutions. The combined results support the key role of gp41 aa 36 to 45 in the development of resistance to ENF and illustrate that additional envelope regions contribute to the ENF susceptibility of fusion inhibitor-naïve viruses and resistance to ENF.

Topics: Amino Acid Substitution; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Microbial Sensitivity Tests; Mutagenesis, Site-Directed; Mutation; Peptide Fragments; Protein Binding

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections; Peptide Fragments

Enfuvirtide (ENF) is the first in a new class of antiretroviral agents targeting the fusion process of the viral life cycle. ENF is a synthetic 36-amino acid peptide that binds to the HR-1 region of gp41 preventing fusion of viral and cellular membranes. With the introduction of ENF there are now four classes of antiretrovirals each with distinct and different resistance pathways. Resistance to ENF among subtype B HIV-1 isolates is associated with amino acid changes mainly in the HR-1 region, although other regions of envelope have also been implicated. To determine whether subtype C viruses developed resistance mutations similar to subtype B viruses, 11 subtype C and 4 subtype B viruses were passaged in the presence of increasing concentrations of ENF. The subtype C isolates showed varying levels of replication at 1 microg/ml ENF by day 18, but by day 29 all replicated efficiently at 10 microg/ml ENF. All subtype C isolates showed evidence of genotypic changes in gp41 HR-1 following exposure to ENF that included G36S/E/D, I37T, V38M/A/L/E, N/S42D, N43K, L45R/M, and A50T/V. Three subtype C viruses had compensatory changes in the HR-2 region, which corresponds to the ENF sequence, and two isolates had changes in the V3 region. Mutational patterns among the four subtype B viruses were similar to those for subtype C and those previously published in the literature. These data indicate that in vitro resistance to ENF develops rapidly among HIV-1 subtype C isolates. In general, mutational patterns for subtype C were similar to those described for subtype B, suggesting that the mechanism of action for ENF is similar for HIV-1 subtype B and C isolates.

Topics: Amino Acid Sequence; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Peptide Fragments; Phylogeny; Sequence Alignment; Serial Passage; Virus Replication

We examined the susceptibility of HIV-1 group M and O isolates to the fusion inhibitors T-20 and T-1249. Unexpectedly, HIV-1 O isolates were as sensitive as group M viruses to inhibition by T-20 but were usually less susceptible to T-1249. Our data suggest that T-20 has broad antiretroviral activity and would be effective in individuals with HIV-1 O infection. However, polymorphisms in gp41 might affect the sensitivity of HIV-1 O to second-generation fusion inhibitors.

Topics: Drug Resistance, Multiple, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Microbial Sensitivity Tests; Peptide Fragments

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments; Reproducibility of Results; Treatment Outcome

Topics: Adenine; Antiretroviral Therapy, Highly Active; Chemistry, Pharmaceutical; Clinical Trials as Topic; Congresses as Topic; Darunavir; Drugs, Investigational; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Nitriles; Organophosphonates; Peptide Fragments; Pyrimidines; Receptors, CCR5; Reverse Transcriptase Inhibitors; Rilpivirine; Societies, Scientific; Sulfonamides; Tenofovir; Zalcitabine

Enfuvirtide (ENF) is the first of a novel class of drugs that blocks HIV fusion to host cells. We analyzed the dynamics of genotypic and phenotypic resistance to ENF during and after long-term ENF therapy and its clinical implications in eight heavily treatment-experienced HIV-infected patients who underwent salvage therapy with enfuvirtide along with other antiretroviral agents. All patients showed a rapid decline in plasma HIV-RNA followed by viral rebound. Changes at codons 36, 42, 43 and/or 44 within the HR1 region of gp41 were selected in all cases, resulting in high-level phenotypic resistance to ENF, ranging from 15- to 445-fold. Both genotypic and phenotypic resistance to ENF rapidly disappeared after discontinuation of the drug, suggesting that ENF-resistant viruses may have an impaired replicative capacity.

Topics: Amino Acid Sequence; Anti-Retroviral Agents; Drug Resistance, Viral; Enfuvirtide; Evolution, Molecular; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Peptide Fragments; Salvage Therapy; Sequence Alignment; Species Specificity

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Denial, Psychological; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Narration; Peptide Fragments

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments

Resistance to enfuvirtide (ENF; T-20), a fusion inhibitor of human immunodeficiency virus type 1 (HIV-1), is conferred by mutations in the first heptad repeat of the gp41 ectodomain. The replicative fitness of recombinant viruses carrying ENF resistance mutations was studied in growth competition assays. ENF resistance mutations, selected in vitro or in vivo, were introduced into the env gene of HIV-1(NL4-3) by site-directed mutagenesis and expressed in HIV-1 recombinants carrying sequence tags in nef. The doubling time of ENF-resistant viruses was highly correlated with decreasing ENF susceptibility (R(2) = 0.859; P < 0.001). Initial fitness experiments focused on mutants identified by in vitro selection in the presence of ENF (L. T. Rimsky, D. C. Shugars, and T. J. Matthews, J. Virol. 72:986-993, 1998). In the absence of drug, these mutants displayed reduced fitness compared to wild-type virus with a relative order of fitness of wild type > I37T > V38 M > D36S/V38 M; this order was reversed in the presence of ENF. Likewise, recombinant viruses carrying ENF resistance mutations selected in vivo displayed reduced fitness in the absence of ENF with a relative order of wild type > N42T > V38A > N42T/N43K approximately N42T/N43S > V38A/N42D approximately V38A/N42T. Fitness and ENF susceptibility were inversely correlated (r = -0.988; P < 0.001). Similar results were obtained with recombinants expressing molecularly cloned full-length env genes obtained from patient-derived HIV-1 isolates before and after ENF treatment. Further studies are needed to determine whether the reduced fitness of ENF-resistant viruses alters their pathogenicity in vivo.

Topics: Cell Line; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Mutation; Peptide Fragments; Recombination, Genetic; Virus Replication

Topics: CD4 Lymphocyte Count; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments; Severity of Illness Index; Treatment Outcome; Viral Load

Topics: Clinical Trials as Topic; Drugs, Investigational; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments

Topics: Anti-HIV Agents; Clinical Trials as Topic; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments

Topics: Adult; Anti-Bacterial Agents; Drug Therapy, Combination; Enfuvirtide; Epidural Abscess; Follow-Up Studies; HIV Envelope Protein gp41; HIV Infections; Homosexuality, Male; Humans; Immunocompromised Host; Injections, Subcutaneous; Male; Peptide Fragments; Risk Assessment; Spondylitis; Thoracic Vertebrae; Treatment Outcome

The peptide fusion inhibitor (PFI) enfuvirtide is the first of a new class of entry inhibitors to receive FDA approval. We previously determined the susceptibility of 55 PFI-naïve-patient isolates to enfuvirtide and a second peptide inhibitor, T-649. Seven of the 55 viral isolates were insusceptible to enfuvirtide, T-649, or both inhibitors in the absence of prior exposure. To determine the molecular basis of the insusceptible phenotypes, we PCR amplified and cloned five PFI-insusceptible and one PFI-susceptible, full-length, biologically functional env genes and characterized viruses pseudotyped with the Env proteins in a single-round drug sensitivity assay. Overall, the mean 50% inhibitory concentrations of enfuvirtide and T-649 for the PFI-insusceptible Env pseudotypes were 1.4 to 1.7 log(10) and 1.2 to 1.8 log(10) greater, respectively, than those for a PFI-susceptible lab strain, NLHX; however, all of the PFI-insusceptible Env proteins conserved the sequence of a critical enfuvirtide interaction site (residues 36 to 38 of gp41, GIV) in HR-1. In contrast, multiple amino acid changes were observed C-terminal to HR-1, many of which were located in regions of HR-2 corresponding to the PFI. Nevertheless, peptides based on patient-derived HR-2 sequences were not more potent inhibitors than enfuvirtide or T-649, arguing that the basis of PFI susceptibility is not a higher-affinity, competitive HR-1/HR-2 interaction. These results demonstrate that regions of Env outside the enfuvirtide interaction site can significantly impact the PFI susceptibility of patient-derived Env, even prior to drug exposure. We hypothesize that both gp120 gene- and gp41 gene-encoded determinants that minimize the window of opportunity for PFI to bind provide a growth advantage and possibly a predisposition to resistance to this new class of drugs in vivo.

Topics: Amino Acid Sequence; Cells, Cultured; Coculture Techniques; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Microbial Sensitivity Tests; Molecular Sequence Data; Peptide Fragments

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

The human immunodeficiency virus type 1 (HIV-1) fusion inhibitor enfuvirtide has recently been introduced into clinical practice and has exhibited efficient anti-HIV-1 activity in combination with other antiretroviral agents. In the present study, we addressed the effect of long-term treatment with enfuvirtide on the intrahost evolution of HIV-1. The genotype and phenotype patterns and the relative replication capacity (rRC) of enfuvirtide-resistant HIV-1 mutants were evaluated in samples from 11 subjects (7 virological nonresponders and 4 responders) who received the compound for more than 1 year in combination with different regimens. Selection of one or more mutations clustering in a sequence (amino acids 36 to 45) of the gp41 N-terminal heptad repeat was observed in samples from the seven virological nonresponders but not in those from responders. In two subjects who discontinued enfuvirtide, reversion of the resistant genotype was detected within 3 months. Recombinant clones bearing mutated gp41 sequences displayed reduced susceptibilities to enfuvirtide, with the 50% inhibitory concentrations (IC(50)s) ranging from 0.6 to 12.8 microg/ml, whereas the IC(50) for isolates with baseline sequences was 0.013 +/- 0.010 microg/ml. Interestingly, long-term monitoring of resistant variants provided evidence that ongoing adaptation to the drug is paralleled by phenotypic changes. A limited drop in the rRC in the absence of drug was observed for clones from four of the seven nonresponders bearing mutations associated with resistance. Overall, the data indicate that the different genotype patterns associated with a detectable degree of HIV-1 resistance to enfuvirtide generated during long-term treatments are characterized by a substantially low genetic barrier, possible ongoing adaptation with increased degrees of resistance, and limited influence on the viral rRC.

Topics: Amino Acid Sequence; CD4 Lymphocyte Count; Cloning, Molecular; Drug Resistance, Viral; Enfuvirtide; Genotype; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Long-Term Care; Molecular Sequence Data; Mutation; Peptide Fragments; Phenotype; Virus Replication

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.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Blood-Testis Barrier; Cyclopropanes; Enfuvirtide; Genitalia, Male; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Organophosphonates; Oxazines; Peptide Fragments; Tenofovir

Topics: Adult; Anti-HIV Agents; Drug Resistance, Multiple, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Mutation; Peptide Fragments; Pregnancy; Pregnancy Complications, Infectious

We analysed the genetic changes in gp41 in a population of 30 heavily pretreated HIV-1-infected patients failing on a T-20-containing salvage therapy. This study confirms the key role of the number of drugs presumed to be still effective associated with T-20 in the magnitude of the virological response. Our results suggest that only HR-1 sequencing is necessary to characterize resistance to T-20, and that HR-2 domain sequencing is probably not required.

Topics: Drug Resistance, Viral; Enfuvirtide; Genes, Viral; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Mutation; Peptide Fragments; Protein Structure, Tertiary; Sequence Analysis, DNA; Treatment Failure

Topics: Anti-Retroviral Agents; CD4 Lymphocyte Count; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; Viral Load

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Viral Load

Topics: Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials, Phase III as Topic; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Long-Term Care; Male; Peptide Fragments; Viral Load

Topics: Desensitization, Immunologic; Drug Hypersensitivity; Enfuvirtide; Follow-Up Studies; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Middle Aged; Peptide Fragments; Risk Assessment

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.

Topics: CD4-Positive T-Lymphocytes; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Infusions, Parenteral; Peptide Fragments

We report a case of successful, rapid desensitization to enfuvirtide after a hypersensitivity reaction in a man with highly drug-resistant human immunodeficiency virus type 1 infection. The patient was desensitized in a monitored intensive care unit and tolerated the rapid desensitization protocol without any serious adverse effects. This case illustrates the ability to safely desensitize patients with limited treatment options who require enfuvirtide therapy.

Topics: Adult; Drug Hypersensitivity; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Peptide Fragments; Remission Induction

Topics: Drug Administration Schedule; Drug Monitoring; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections, Subcutaneous; Patient Education as Topic; Patient Selection; Peptide Fragments

Topics: Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments

Topics: Clinical Trials as Topic; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections; Peptide Fragments; Treatment Outcome

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).

Topics: Amino Acid Sequence; Amino Acid Substitution; DNA, Complementary; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Italy; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Peptide Fragments; Recombination, Genetic; RNA, Viral; Selection, Genetic; Sequence Analysis, DNA; Virus Replication

Topics: Drug Approval; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments; Randomized Controlled Trials as Topic

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Patient Selection; Peptide Fragments

HIV-infected patients who stand to benefit most from the availability of new antiretrovirals are those who have the fewest treatment options. Clinical trials have shown that in antiretroviral-experienced patients requiring a regimen change, including an antiretroviral drug from a previously unused class, is associated with greater treatment response. In clinical trials of the entry inhibitor enfuvirtide, triple-class-experienced patients treated with enfuvirtide plus an optimized background regimen of 3 to 5 active antiretrovirals consistently showed virologic and immunologic responses superior to those of the patients who received optimized background treatment alone, regardless of the number of active antiretroviral drugs included in the optimized background treatment. Adverse events have not been observed to be considerably greater among enfuvirtide-treated patients than among those receiving optimized background treatment alone. Injection site reactions of mostly mild to moderate severity were the most common adverse events in the enfuvirtide group, with few resulting in discontinuation.

Topics: Anti-Retroviral Agents; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments; Treatment Failure

Topics: Africa; Anti-HIV Agents; Drug Industry; Enfuvirtide; Europe; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; United States

The most significant new information about anti-HIV drugs offered in Barcelona concerned those drugs that are either already available or which will soon be available. This includes new information about T-20 (now called enfuvirtide or Fuzeon) and atazanavir--two drugs which will likely be approved within the next six months. Another new drug likely to be approved soon is FTC (Coviracil), a close relative of 3TC (lamivudine, Epivir), though its importance is less certain than that of enfuvirtide and atazanavir. Important new information was also released about tenofovir (Viread), a drug approved by the FDA late in 2001. Equally important were new observations about some older drugs, particularly the combination of ddI and d4T. Many comparative studies of different drug combinations were also reported, offering new information about the relative value of a number of treatment strategies.

Topics: Anti-HIV Agents; Atazanavir Sulfate; CD4 Lymphocyte Count; Deoxycytidine; Drug Approval; Drug Design; Emtricitabine; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Oligopeptides; Peptide Fragments; Pyridines; United States; United States Food and Drug Administration; Viral Load

Primary resistance mutations to fusion inhibitors and polymorphisms in gp41 sequences of non-B subtypes and recombinant HIV-1 isolates were analysed. L91H to RPR103611 was detected in one DGpol/Denv/Dgp41 recombinant; L9F and K144R, rarely reported previously, were frequent in the B region of CRF14_BG recombinants. V194I and V318A, not described in the G subtype, were detected in the G region of BG recombinants and in G subtype viruses that also show the rare mutations T115L, M118V and K90R.

Topics: Anti-HIV Agents; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Mutation; Peptide Fragments; Polymorphism, Genetic

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: Drug Approval; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; United States; United States Food and Drug Administration

Topics: Anti-HIV Agents; Clinical Trials as Topic; Drug Approval; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; United States; United States Food and Drug Administration; Viral Load

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Viral Load

Topics: Anti-HIV Agents; Drug Costs; Enfuvirtide; Health Services Accessibility; HIV Envelope Protein gp41; HIV Infections; Humans; Patient Compliance; Peptide Fragments

Topics: Enfuvirtide; Female; Half-Life; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Peptide Fragments; Randomized Controlled Trials as Topic

Topics: Drug Costs; Drug Industry; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Medical Assistance; Peptide Fragments

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.

Topics: Adult; Clinical Trials as Topic; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Peptide Fragments; Treatment Outcome; Viral Load

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.

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections; Nurse-Patient Relations; Patient Compliance; Patient Education as Topic; Peptide Fragments

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: Drug Costs; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; RNA, Viral; United States

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

Enfuvirtide (T-20) is the lead compound of the new class of antiretroviral drugs called fusion inhibitors. T-20 resistance-associated mutations located in the heptad repeat 1 (HR-1) domain of gp41 have been described in vitro and in clinical trials. In this study, the authors investigated the primary genotypic T-20 resistance in subtype B and non-B HIV-1 strains from patients at the beginning of their follow-up in the Luxembourg HIV Cohort as well as the emergence of primary resistance to T-20 in patients who had long-term infection with subtype B HIV-1 strains. HR-1 fragments including the gp41 amino acid 36-45, T-20-sensitive region were screened for amino acid variation. No classic T-20 resistance-associated mutations were identified in subtype B or non-B isolates. However, several uncommon mutations were found at residues 37, 39, and 42 for subtype B isolates and at residue 42 for a subtype non-B isolate. The results indicate that primary genotypic T-20 resistance seems to be rare in HIV-1, regardless of subtype or prior antiretroviral therapy (excluding fusion inhibitors). However, episodic variation within HR-1 can occur and needs further phenotypic evaluation in accurate fusion inhibitor resistance assays.

Topics: Anti-HIV Agents; Cohort Studies; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation; Peptide Fragments; Sequence Alignment; Time Factors

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections, Subcutaneous; Patient Education as Topic; Peptide Fragments; Reimbursement Mechanisms; United States; United States Food and Drug Administration

Topics: Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections, Subcutaneous; Peptide Fragments; Salvage Therapy; United States; United States Food and Drug Administration

Topics: Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments

Topics: Anti-HIV Agents; Drug Approval; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; United States

Topics: Adult; Anti-HIV Agents; Child; Dose-Response Relationship, Drug; Drug Resistance, Viral; Enfuvirtide; Fees, Pharmaceutical; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Randomized Controlled Trials as Topic

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; Clinical Trials as Topic; Enfuvirtide; Ganciclovir; Hepatitis B; HIV Envelope Protein gp41; HIV Infections; Humans; Organophosphonates; Organophosphorus Compounds; Peptide Fragments; Tenofovir; Valganciclovir

Topics: Adolescent; Adult; Child; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments; United States; United States Food and Drug Administration

Topics: Adult; Anti-HIV Agents; Child; Drug Approval; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Peptide Fragments; United States; United States Food and Drug Administration

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: Drug Resistance; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments

Topics: Adult; Anti-HIV Agents; Child; Clinical Trials as Topic; Drug Approval; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Legislation, Drug; Peptide Fragments; United States; United States Food and Drug Administration

In March 2003, enfuvirtide was approved in the USA and the European Union for the treatment of patients with HIV infection who have experienced failure or intolerable side effects of treatment with at least one representative of each antiretroviral drug class. Enfuvirtide has a new mode of action: it binds to the viral envelope glycoprotein 41 that is involved in the fusion of the virus to the membrane of the CD4 T cell. In two large phase III studies, 90 mg of enfuvirtide administered twice daily subcutaneously in addition to a background treatment of other antiretroviral drugs, had a significant favourable effect on both the plasma viral load (decrease) and the CD4 counts (increase) compared to the background treatment alone. Disadvantages of treatment with enfuvirtide are its subcutaneous administration (98% of the patients had local adverse reactions) and the high costs involved (1500 euro per patient per month).

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Viral Load

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

Topics: Clinical Trials as Topic; Drug Approval; Enfuvirtide; European Union; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Peptide Fragments; Prognosis; Treatment Outcome; United States; United States Food and Drug Administration

We evaluated the in vitro anti-human immunodeficiency virus type 1 (HIV-1) interactions between 1-beta-D-2,6-diaminopurine dioxolane (DAPD) and enfuvirtide (T-20) against clinical isolates sensitive and resistant to reverse transcriptase and protease inhibitors. Interactions between T-20 and DAPD were synergistic to nearly additive, with combination index values ranging from 0.53 to 1.06 at 95% inhibitory concentrations. These studies suggest that a combination of T-20 and DAPD might be useful in the treatment of antiretroviral drug-experienced patients.

Topics: Anti-HIV Agents; Dioxolanes; Drug Resistance, Viral; Drug Synergism; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Peptide Fragments; Purine Nucleosides; Reverse Transcriptase Inhibitors

Topics: Clinical Trials as Topic; Drug Therapy, Combination; Enfuvirtide; HIV; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments

Topics: Cost-Benefit Analysis; Drug Resistance; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments

In a combined analysis from TORO-1 and TORO-2, T-20 remains effective as "deep salvage" out to 48 weeks.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Salvage Therapy; Viral Load

Topics: Anti-HIV Agents; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Salvage Therapy; Viral Load

Topics: AIDS-Related Opportunistic Infections; Clinical Trials, Phase III as Topic; Costs and Cost Analysis; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Peptide Fragments; Pneumonia, Bacterial

In-vitro differences in T-20 susceptibility among HIV-1 subtypes have been reported. We therefore studied the T-20 binding domain of a variety of virus subtypes from both antiretroviral-naive and -experienced patients. Minimal variation in the HR-1 region of gp41 was observed, especially within the region responsible for T-20 resistance. Any subtype differences in T-20 susceptibility do not appear to be related to HR-1 genetic variation.

Topics: Anti-HIV Agents; Base Sequence; DNA Primers; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments

T-20 is a novel antiretroviral agent that inhibits the fusion of human immunodeficiency virus (HIV) with target cell membranes. It is delivered by self-administered, twice-daily, subcutaneous injections. The impact of this mode of administration on patients' ability to conduct normal activities of daily living (ADL) and comply with a T-20 treatment regimen was assessed as part of a 48-week, phase 2 trial (T20-205). Patients' opinions on the impact of T-20 on ADL, ease of use of T-20, and choice to continue with T-20 were assessed by two questionnaires completed at baseline and week 48 (or study withdrawal). ADL were measured using a Likert-type scale based on established instruments with questions added to assess HIV-specific issues. Seventy previously treated patients received T-20 in combination with an average of five oral antiretroviral agents. Relative to other HIV/AIDS drugs, T-20 had little impact on ADL, with the majority of patients (54%-96%) agreeing (somewhat or strongly) that subcutaneous injections had not limited ADL. Patients found the injections relatively easy to perform with more than 47% of patients stating that each aspect of the injections (ease of injection, storage, reconstitution, and disposal of sharps) were very easy or easy. If medically indicated, 98% of patients stated that they would choose to continue with T-20. The most common reasons for this were the perceived effectiveness of T-20 and lack of side effects. In conclusion, the need to deliver T-20 via twice-daily subcutaneous injections was not considered an important barrier by HIV-positive patients seeking improvement or stabilization of their condition.

Topics: Activities of Daily Living; Adult; Anti-HIV Agents; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Injections, Subcutaneous; Male; Patient Satisfaction; Peptide Fragments; Self Administration; Surveys and Questionnaires

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

Topics: Anti-HIV Agents; Drug Approval; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; United States; United States Food and Drug Administration

Topics: Anti-HIV Agents; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Membrane Fusion; Mutation; Peptide Fragments

Topics: Anti-HIV Agents; Centers for Disease Control and Prevention, U.S.; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; United States

Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; Clinical Trials, Phase III as Topic; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Infections; Peptide Fragments; Virus Integration

We asked a leading HIV physician to summarize some of the treatment issues that clinicians are now looking at after the Barcelona conference. Topics in this interview include: Tenofovir, including first-line therapy; The shift from protease inhibitors to non-nucleoside RT inhibitors, for many but not all patients; Benefits of once-a-day regimens; Lipodystrophy, and strategies for avoiding or reducing it; Viral resistance testing; T-20; Prevention--including danger of superinfection with a new HIV strain.

Topics: Anti-HIV Agents; Drug Administration Schedule; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Lipodystrophy; Peptide Fragments; Spain

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclic N-Oxides; Drugs, Investigational; Enfuvirtide; Furans; HIV; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; HIV Integrase Inhibitors; Humans; Nitriles; Oximes; Peptide Fragments; Piperazines; Piperidines; Pyridazines; Pyridines; Pyrimidines; Reverse Transcriptase Inhibitors; Triazoles

The synthetic peptide T-20 (enfuvirtide) represents the first of a new class of antiretroviral compounds to demonstrate in vivo potency by targeting a step in viral entry. T-20 inhibits a conformational change in the human immunodeficiency virus type 1 (HIV-1) transmembrane glycoprotein (gp41) that is required for fusion between HIV-1 and target cell membranes. The initial phase I clinical trial of T-20 treatment for HIV-infected patients thus provided a unique opportunity to evaluate the emergence of resistant virus in vivo to this novel class of antiretroviral agents. All four patients who received an intermediate dose of T-20 (30 mg twice daily) had an initial decline in plasma viral load over the first 10 days but a rising trend by day 14, suggestive of selection for resistant virus. Plasma virus derived from patients enrolled in all dosage groups of the phase I T-20 trial was analyzed by population sequencing before and after treatment. While no mutations were found within a highly conserved 3-amino-acid sequence (GIV) known to be critical for fusion at baseline, after 14 days of therapy, virus from one patient in the 30-mg dose group (30-1) developed a mutation in this motif, specifically an aspartic acid (D) substitution for glycine (G) at position 36. Multiple env clones were derived from the plasma virus of all four patients in the 30-mg dosage group. Sequence analysis of 49 clones derived from the plasma of patient 30-1 on day 14 revealed that 25 clones contained the G36D mutation, while 8 contained the V38A mutation. Dual mutations involving G36D and other residues within the HR1 domain were also identified. In 5 of the 49 env clones, other mutations involving residues 32 (Q32R or Q32H) and 39 (Q39R) were found in combination with G36D. Cloned env sequences derived from the plasma virus of subject 30-3 also had single mutations in the GIV sequence (V38M and I37V) detectable following therapy with T-20. The plasma virus from subjects 30-2 and 30-4 did not contain changes within the GIV sequence. To analyze the biological resistance properties of these mutations, we developed a novel single-cycle HIV-1 entry assay using JC53BL cells which express beta-galactosidase and luciferase under control of the HIV-1 long terminal repeat. Full-length env clones were derived from the plasma virus of patients 30-1 and 30-3 and used to generate pseudotyped virus stocks. The mean 50% inhibition concentrations (IC(50)s) for mutants G36D and V38A (patient 30-1) w

Topics: Amino Acid Sequence; Anti-HIV Agents; Cloning, Molecular; Drug Resistance, Microbial; Enfuvirtide; Enzyme-Linked Immunosorbent Assay; Genes, env; Genes, Reporter; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutagenesis, Site-Directed; Peptide Fragments; Phenotype; RNA, Viral; Viral Load

Topics: AIDS Vaccines; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Antigens; Clinical Trials as Topic; Cyclic N-Oxides; Enfuvirtide; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; Humans; Membrane Fusion; Oximes; Patient Compliance; Peptide Fragments; Piperidines; Pyridines; Receptors, HIV

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV Protease Inhibitors; Humans; Peptide Fragments; Reverse Transcriptase Inhibitors

Human immunodeficiency virus type 1 (HIV-1) entry proceeds via a cascade of events that afford promising targets for therapy. PRO 542 neutralizes HIV-1 by blocking its attachment to CD4 cells, and T-20 blocks gp41-mediated fusion. Both drugs have shown promise in phase 1/2 clinical trials. Here, the drugs were tested individually and in combination in preclinical models of HIV-1 infection, and inhibition data were analyzed for cooperativity by using the combination index method. Synergistic inhibition of virus-cell and cell-cell fusion was observed for phenotypically diverse viruses for a broad range of drug concentrations, often resulting in > or = 10-fold dose reductions in vitro. Additional mechanism-of-action studies probed the molecular basis of the synergies. The markedly enhanced activity observed for the PRO 542:T-20 combination indicates that the multistep nature of HIV-1 entry leaves the virus particularly vulnerable to combinations of entry inhibitors. These findings provide a strong rationale for evaluating combinations of these promising agents for therapy in vivo.

Topics: Animals; Anti-HIV Agents; CD4 Immunoadhesins; Cell Fusion; Cell Line; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Drug Synergism; Enfuvirtide; Eukaryotic Cells; HeLa Cells; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Peptide Fragments; T-Lymphocytes; Virus Replication

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Enfuvirtide; Forecasting; HIV Envelope Protein gp41; HIV Infections; HIV Integrase Inhibitors; Humans; Peptide Fragments; Salvage Therapy

Topics: Anti-HIV Agents; Cross-Sectional Studies; Drug Resistance, Microbial; Enfuvirtide; Genotype; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Peptide Fragments; Time Factors

The viral envelope glycoprotein gp41 mediates membrane fusion in HIV/SIV infection. gp41 ectodomain (e-gp41, residues 27-149), which was shown to interact with phospholipid membranes, exists in an equilibrium between the monomeric and trimeric states. Here, we analyzed, by intrinsic Trp fluorescence and resonance energy transfer, whether SIV e-gp41-membrane interaction depends on the gp41 oligomeric state. We found that both gp41 monomers and trimers bind membranes, with the monomers' full binding being reached at substantially lower lipid to protein ratios. Furthermore, the different characteristics of the Trp fluorescence of monomers and trimers enabled us to detect binding of each form at concentrations at which both species were present. CD spectroscopy revealed that the secondary structure of gp41 monomers does not change upon membrane binding, suggesting that membrane-bound monomeric-gp41 is a possible target for DP-178, a potent peptide inhibitor of HIV infection. The consequences of the interaction between monomeric and trimeric gp41 with membranes in HIV/SIV infection, its inhibition, and its associated neuropathologies are discussed.

Topics: Anti-HIV Agents; Circular Dichroism; Energy Transfer; Enfuvirtide; Fluorescence; HIV Envelope Protein gp41; HIV Infections; HIV-1; Liposomes; Membrane Glycoproteins; Peptide Fragments; Phospholipids; Protein Binding; Protein Structure, Quaternary; Protein Structure, Secondary; Retroviridae Proteins; Simian Immunodeficiency Virus

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Canada; Clinical Trials as Topic; Enfuvirtide; Female; HIV; HIV Envelope Protein gp41; HIV Infections; Humans; Male; Membrane Fusion; Peptide Fragments

Topics: Anti-HIV Agents; Clinical Trials, Phase III as Topic; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Patient Selection; Peptide Fragments; United States

Topics: Anti-HIV Agents; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Peptide Fragments; Pyrimidinones; South Africa

The N- (N36/DP107) and C-terminal peptides (C34/DP178) from two alpha-helical domains of human immunodeficiency virus type 1 (HIV-1) gp41 inhibited HIV infection. A single-round infection using pseudotyped virus clarified that a greater amount of gp41-derived peptides was necessary for the inhibition of R5 virus (ADA) infection than for that of X4 virus (LAI) infection. Furthermore, R5X4 virus (89.6) infection via CCR5 needs more peptides for inhibition than its infection via CXCR4 does. A high sensitivity of X4 virus was partially ascribed to the inhibition of the 12G5 binding to CXCR4 by DP178LAI.

Topics: Amino Acid Sequence; Anti-HIV Agents; Astrocytes; CD4 Antigens; Cell Line; Enfuvirtide; Genes, Reporter; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Kidney; Luciferases; Molecular Sequence Data; Peptide Fragments; Receptors, CCR5; Receptors, CXCR4; Transfection

T-20 (pentafuside) is the first of a new category of anti-HIV drugs, called fusion inhibitors, that has undergone testing in clinical trials. The drug was developed by Trimeris, Inc. in collaboration with Hoffman-La Roche, Inc. and works by blocking the fusions of HIV to the host cells. Results of a Phase II clinical trial showed that 60 percent of heavily pretreated participants had a significant drop in viral load. Some mild to moderate side effects were noted, including headache, nausea, and fever. T-20 is administered by injection twice daily and is only effective against HIV-1, the virus most prevalent in this hemisphere. Pediatric trials of T-20 were announced in November. T-1249, another fusion inhibitor developed by Trimeris, is in Phase I clinical trials. Contact information for the treatment advocates at Women Alive is given.

Topics: Adult; Anti-HIV Agents; Child; Clinical Trials, Phase II as Topic; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Peptide Fragments

Topics: CD4-Positive T-Lymphocytes; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Membrane Fusion; Peptide Fragments; Receptors, CCR5; Receptors, CXCR4

Topics: CD4 Lymphocyte Count; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Membrane Fusion; Peptide Fragments; Viral Load

Human immunodeficiency virus type 1 (HIV-1) envelope protein gp41 mediates viral fusion with human host cells. The peptide segment T20/DP178, located in the C-terminus of the ectodomain of gp41, interacts with the N-terminal leucine zipper-like domain on gp41 to establish the fusogenic conformation of the virus. Synthetic T20/DP178 peptide is highly efficacious in inhibiting HIV-1 infection in vitro by disrupting the transformation of fusogenic status of viral gp41; thus, it has been proposed for clinical trial. We report that synthetic T20/DP178 is a chemoattractant and activator of human peripheral blood phagocytes but not of T lymphocytes. We further demonstrate that T20/DP178 specifically activates a seven-transmembrane, G-protein-coupled phagocyte receptor for N-formylated chemotactic peptides, formyl peptide receptor (FPR). Moreover, synthetic T20/DP178 analogs lacking N-terminal amino acids acted as FPR antagonists. Our results suggest that gp41 peptides regulate phagocyte function via FPR and identify a novel mechanism by which HIV-1 may modulate innate immunity.

Topics: Cells, Cultured; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Monocytes; Neutrophils; Peptide Fragments; Phagocytosis; Receptors, Formyl Peptide; Receptors, Immunologic; Receptors, Peptide; Virus Replication

Topics: Anti-HIV Agents; Clinical Trials, Phase II as Topic; Controlled Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Patient Selection; Peptide Fragments; United States

Topics: Adenine; AIDS Vaccines; Anti-HIV Agents; Enfuvirtide; Granulocyte-Macrophage Colony-Stimulating Factor; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; Humans; Interleukin-2; Organophosphonates; Peptide Fragments; Ritonavir

Many at the 6th Conference on Retroviruses and Opportunistic Infections expressed concern regarding the significant amount of drug resistance that is developing among treatment-naive patients. The threat of drug failure has created an acute need for new treatments that are not affected by resistance to older treatments. Three promising drugs that are on the horizon are discussed. Amprenavir (Agenerase) is expected to receive marketing approval in the next few months, and ABT-378 and T-20 are in phase II trials and should be available in the next 2 years. Additional information on these drugs is presented.

Topics: Anti-HIV Agents; Carbamates; Congresses as Topic; Drug Resistance, Microbial; Drug Therapy, Combination; Drugs, Investigational; Enfuvirtide; Furans; HIV Envelope Protein gp41; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Peptide Fragments; Pyrimidinones; Salvage Therapy; Sulfonamides; Viral Load; Virus Replication

T-20 is the most prominent of the new class of anti-HIV drugs, the fusion inhibitors. The drug, manufactured by Timeris, Inc., has extremely potent antiviral activity, and attacks HIV at a different point in its replication cycle than current antiretrovirals. T-20 is injected intravenously or taken by subcutaneous infusion. In the largest human clinical trial of the drug, researchers found it was well-tolerated, and reduced viral load to undetectable levels in the group administered the highest dosage. Although results are promising, drug administration is a concern, and researchers are working on a similar version that may be administered orally. Several trials of T-20 are underway or enrolling, and contact information is provided.

Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Pilot Projects; Randomized Controlled Trials as Topic; Treatment Outcome; Viral Load

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

Topics: Anti-HIV Agents; Chemokine CCL5; Chemokines; Developed Countries; Developing Countries; Disease Outbreaks; Enfuvirtide; Gene Products, tat; Global Health; HIV; HIV Envelope Protein gp41; HIV Infections; Humans; Interferon-alpha; Peptide Fragments; Receptors, HIV; tat Gene Products, Human Immunodeficiency Virus; Virus Replication

Trimeris, Inc. is developing a new class of HIV treatment, T-20 (pentafuside), known as a fusion inhibitor. Using a viral sequence from the actual HIV virus, researchers developed T-20 (a 36-amino acid portion of gp41) to inhibit the virus from binding to, entering, and infecting healthy cells. T-20 also blocks infected cells from fusing with uninfected cells. T-20 shows a high degree of antiviral activity, no toxicity, and a low chance of developing cross resistance. It is effective against all known strains of HIV-1 and the technology may lead to development of drugs effective against other enveloped viruses. Viral resistance is not likely to develop because T-20 was produced from a segment of the HIV virus that is constant from one strain to another. Additionally, the T-20 sequence in gp41 has to bind to a complementary sequence in gp41, ruling out most mutations that cause resistance because they are unlikely to occur in matched pairs. T-20 is targeted to be dispensed continuously by a portable infusion pump, reducing how much T-20 is needed. A phase I trial of four patients showed increased CD4 counts for larger doses, 30 mg and 100mg doses, but not at smaller doses. A larger trial of forty patients who have failed at least one protease inhibitor is planned. Further trials are proposed for children, treatment-naive adults, and adults with high viral loads. T-20 can also be used for short-term treatment to reduce drug side effects or to prevent maternal/fetal transmission early in gestation. Trimeris will apply for marketing approval early in 2000.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Industry; Drug Resistance, Microbial; Drugs, Investigational; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Injections, Subcutaneous; Peptide Fragments; United States; Virus Replication

T-20, a fusion inhibitor comprised of a portion of the gp41 protein, lowers viral loads by as much as 97 percent. Because T-20 confers no cross-resistance with currently used antivirals, T-20 is a good candidate for use as a salvage therapy. T-20 is planned to be administered by subcutaneous infusion pump to 72 patients who are NNRTI-naive and have failed indinavir, ritonavir, or nelfinavir. Initially, T-20 will be given alone, then in combination with efavirenz and nelfinavir plus either saquinavir or ritonavir. Concerns that HIV can easily become resistant to T-20, as observed in cell cultures, would potentially leave some trial participants with limited treatment options. Gilead Sciences, manufacturers of adefovir, has enlarged the access program for adefovir to include individuals who have failed two nucleoside analogs and at least one protease inhibitor. Gilead strongly recommends that study participants routinely have kidney tests, as higher doses of the drug have produced signs of Fanconi-like syndrome.

Topics: Adenine; Anti-HIV Agents; Clinical Trials as Topic; Drug Costs; Drug Resistance, Microbial; Drug Therapy, Combination; Drugs, Investigational; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Infusions, Intravenous; Peptide Fragments; Salvage Therapy

T-20, a 36-amino acid peptide, is designed to block a previously unstudied critical step in the process by which HIV fuses to and enters cells. In a small human trial, volunteers received 4 different doses of T-20 every 12 hours for 14 days. The highest dose resulted in a viral load decrease of at least 1.5 logs, with a CD4 count increase of 52; these results may be even greater, considering the drug was only used for 2 weeks. One disadvantage of T-20 is that it must be either injected or administered by continuous infusion to keep the level high enough in the body. Side effects and whether T-20 is tolerable and effective in long-term use are not known at this time.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Administration Routes; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Viral Load