A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy

Lalezari, Jacob; Eron, Joseph J.; Carlson, Margrit; Cohen, Calvin; DeJesus, Edwin; Arduino, Roberto C.; Gallant, Joel E.; Volberding, Paul A.; Murphy, Robert L.; Valentine, Fred; Nelson, Emily L.; Sista, Prakash; Dusek, Alex; Kilby, J. Michael

doi:10.1097/00002030-200303280-00007

Cited by 137 publications

(92 citation statements)

References 26 publications

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“…Although several HIV-1 entry inhibitors have been evaluated in clinical trials and have shown promising prospects for therapy (1,28), the only entry inhibitor licensed to date is the fusion inhibitor enfuvirtide (ENF; also called T20), which has shown potent antiviral activity in patients, resulting in sustained viral load reduction when used in combination with an optimized background regimen of protease and/or reverse transcriptase inhibitors (21)(22)(23). Similar to results with other antiviral agents, however, ENF-resistant HIV-1 variants may emerge under the selective pressure of ENF (26,32,39,42) whenever the treatment fails to completely suppress viral replication in vivo.…”

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confidence: 99%

Role of the Envelope Genetic Context in the Development of Enfuvirtide Resistance in Human Immunodeficiency Virus Type 1-Infected Patients

Labrosse

Morand‐Joubert

Goubard

et al. 2006

J Virol

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Acquired human immunodeficiency virus type 1(HIV-1) resistance to the fusion inhibitor enfuvirtide (ENF)is primarily associated with mutations within the highly conserved first heptad repeat (HR1) region of gp41. Viral env sequences, however, are remarkably variable, and the envelope genetic background could have an important impact on optimal expression of HR1 mutations. We have examined the genetic evolution of env sequences, ENF susceptibility, and Env replicative capacity in patients failing ENF treatment. Sequential plasma-derived virus populations, obtained from six patients initiating ENF treatment as part of a salvage therapy, were studied using a recombinant phenotypic assay evaluating the entire gp120 and the gp41 ectodomains. Regardless of major differences in the baseline ENF susceptibilities, viral populations with similar phenotypic ENF resistance (50% inhibitory concentration, >3,000 ng/ml) were selected under treatment in four of six patients. As expected, in all patients ENF-resistant viruses harbored one or more HR1 mutations (positions 36, 38, and 43). Interestingly, in five patients the emergence of resistance mutations was not associated with reduced Env replicative capacity. Phylogenetic analysis of env sequences in sequential samples from two patients showed that the HR1 mutations had emerged in the context of env quasi-species that were different from those prevalent at baseline. Thus, the envelope genetic context appears to play a critical role in the selection of HR1 mutations and the expression of ENF resistance, thereby conditioning the evolution of HIV-1 under fusion inhibitor selective pressure.Considerable effort is currently being devoted to the development of antiviral agents able to prevent human immunodeficiency virus type 1 (HIV-1) entry into target cells. The HIV-1 entry process is mediated by the trimeric viral envelope glycoproteins (Env) exposed at the surface of the virion (45). The HIV-1 entry is a multistep process (11,14,45). The sequential interaction of the surface subunit, gp120, with CD4 and a chemokine receptor (CCR5 or CXCR4) exposed on the cell membrane triggers conformational changes in the ectodomain of the transmembrane subunit, gp41, which ultimately lead to fusion between the viral and host cell membranes. Like most of the retroviral transmembrane proteins, the ectodomain of gp41 contains an N-terminal fusion peptide followed by two heptad repeat domains (HR1 and HR2), which are connected by a non-helical loop region of 25 to 30 amino acids. Membrane fusion is currently thought to result from the insertion of the fusion peptide into the cellular membrane, and the formation of a six-helix bundle in which the central trimeric HR1 coiled-coil forms three hydrophobic grooves onto which three HR2 domains pack in reverse orientation (4,5,40,43).Although several HIV-1 entry inhibitors have been evaluated in clinical trials and have shown promising prospects for therapy (1, 28), the only entry inhibitor licensed to date is the fusion inhibitor enfuvirtide (ENF; als...

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confidence: 99%

Role of the Envelope Genetic Context in the Development of Enfuvirtide Resistance in Human Immunodeficiency Virus Type 1-Infected Patients

Labrosse

Morand‐Joubert

Goubard

et al. 2006

J Virol

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“…Thompson et al (2006) measure the steady state pharmacokinetic properties of enfuvirtide administered 90 mg bid and 180 mg qd in ∼20 patients. Lalezari et al (2003b) report similar data for 45 mg bid from ∼70 patients. We reproduce the reported mean steady state concentration-time data in Fig.…”

Section: Subcutaneous Administrationmentioning

confidence: 61%

“…6A) may lie within the uncertainties. We also compare our model predictions with reported values of C max , C trough , and AUC for the 45 mg bid (Lalezari et al, 2003b), 90 mg bid, and the 180 mg qd dosing regimens (Fig. 7).…”

Section: Subcutaneous Administrationmentioning

confidence: 95%

“…Model predictions of the time-evolution of the concentration of enfuvirtide in plasma, C p , (lines) obtained by solving Eqs. 10-12 compared with experimental data (symbols) following the administration of multiple subcutaneous doses of (A) 45 mg bid (Lalezari et al, 2003b) (B) 90 mg bid and (C) 180 mg qd . The parameter values employed are listed in Table 1.…”

Section: Appendixmentioning

confidence: 99%

“…The experimental data is shifted in time to coincide with a dosing interval after a steady state concentration profile is achieved. Comparison of model predictions (lines) and experimental observations (symbols) (Lalezari et al, 2003b;Thompson et al, 2006) of the steady state maximum plasma concentration, C max (long dashed line, squares), the trough concentration, C trough (dashed line, circles), and the area under the concentration-time curve, AUC (solid line, diamonds), of enfuvirtide as a function of dosage, D, following (A) twice-daily and (B) once-daily subcutaneous administration. (Figs.…”

Section: Appendixmentioning

confidence: 99%

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Mechanism-based model of the pharmacokinetics of enfuvirtide, an HIV fusion inhibitor

Mohanty

Dixit

2008

Journal of Theoretical Biology

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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.

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GLUE That Sticks to HIV: A Helix‐Grafted GLUE Protein That Selectively Binds the HIV gp41 N‐Terminal Helical Region

et al. 2014

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Methods for the stabilization of well-defined helical peptide drugs and basic research tools have received considerable attention in the last decade. Here, we report the stable and functional display of an HIV gp41 C-peptide helix mimic on a GRAM-Like Ubiquitin-binding in EAP45 (GLUE) protein. C-peptide helix-grafted GLUE selectively binds the N-terminal helical region of gp41, a well-established HIV drug target, in a complex cellular environment. Additionally, the helix-grafted GLUE is folded in solution, stable in human serum, and soluble in aqueous solutions, and thus overcomes challenges faced by a multitude of peptide drugs, including those derived from HIV gp41 C-peptide.

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A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy

Abstract: 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.

Cited by 137 publications

References 26 publications

Role of the Envelope Genetic Context in the Development of Enfuvirtide Resistance in Human Immunodeficiency Virus Type 1-Infected Patients

Role of the Envelope Genetic Context in the Development of Enfuvirtide Resistance in Human Immunodeficiency Virus Type 1-Infected Patients

Mechanism-based model of the pharmacokinetics of enfuvirtide, an HIV fusion inhibitor

GLUE That Sticks to HIV: A Helix‐Grafted GLUE Protein That Selectively Binds the HIV gp41 N‐Terminal Helical Region

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