Enfuvirtide  and Other Fusion Inhibitors

 

Rami Kantor, M.D., Gene D. Morse, Pharm.D.

 

INTRODUCTION

               In the past 2 decades, the available antiretroviral therapy for HIV/AIDS has been designed to inhibit 2 key HIV enzymes: reverse transcriptase (RT) and protease. Despite the immense success of treatment regimens with these drugs and the morbidity and mortality reductions in HIV infected persons (54, 56, 66), the durability of viral suppression is often limited. Contributing factors include poor penetration into protected sites containing a reservoir of HIV (38, 46), alterations in the bioavailability and metabolism of antiretroviral drugs (25), the need of adequate adherence to complex drug regimens (11,17), drug toxicity, and most importantly the emergence of drug resistance viruses (59), resulting in multi-drug resistance and cross resistance, and few or no future therapeutic options.

               The management of individuals infected with a drug resistant virus who are failing antiretroviral therapy is a major challenge in clinical practice, and is more successful if an agent from a class of antiretroviral drugs to which the patient has not previously been exposed is included in the regimen. In the past decade, novel therapies intended to inhibit HIV-1 entry into infectable cells have been investigated (41), including interference with attachment of the virus to the cell, chemokine co-receptor interaction and virus-cell membrane fusion (53).

               Enfuvirtide is the entry inhibitor in the most advanced clinical development, and it represents the first of a new class of antiretroviral compounds to demonstrate in vivo potency by targeting a step in viral entry. This agent has been shown to provide a benefit when given as part of a salvage regimen for persons with drug-resistant HIV-1, who currently have limited therapeutic options. In this chapter, the writing of which is adjacent to the FDA approval of enfuvirtide for clinical use in March 13, 2003 (1), we review and summarize the very recent scientific data on this drug and drug-class.

 

CLASS

Chemical Structure

               Enfuvirtide (T-20, Fuzeon, Pentafuside, DP-178) is a linear 36 amino-acid peptide (molecular mass 4.492 Da) with the following primary amino acid sequence: CH3CO-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln-Asn-Gln-Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-NH2 (1,68). This agent is produced synthetically in a process involving more than 100 steps (as compared with 8-12 steps for a typical anti-HIV medication) to give a powder for subcutaneous (SC) injection (43). The peptide is derived from a naturally occurring motif within the second heptad-repeat domain (HR2) of gp41 transmembrane glycoprotein of a laboratory strain of HIV-1 (LAI) (49).

Structure-Activity Relationship

               Based on its structure, enfuvirtide binds to a region of the gp41 subunit of the HIV-1 envelope glycoprotein (first heptad repeat domain – HR1), that mediates a conformational change required for viral and host-cell membrane fusion. This conformational change is essential to bring the viral and cellular membranes into close enough proximity for fusion and subsequent viral entry into the host-cell. Enfuvirtide prevents this step and thus also the infection of the cell by HIV-1 (see also 'Mechanisms of Action' below).

 

ANTIVIRAL ACTIVITY

               In the original report which suggested a synthetic gp41 peptide as a potent inhibitor of virus-mediated cell-cell fusion (68), Wild et al. reported a 50% inhibitory concentration (IC50) of approximately 1.7 ng/ml. Since then, in vitro activity of enfuvirtide was examined in CD4+ cells infected with HIV-1 laboratory and clinical isolates. IC50 measurements for enfuvirtide in laboratory and primary isolates representing HIV-1 clades A to G ranged from 18 to 1260 ng/ml, and those for baseline clinical isolates ranged from 0.4 to 480 ng/ml (cMAGI assay) and from 3 to 7530 ng/mL (recombinant phenotypic assay) (1,45).

               The viral-host cell fusion process may occur at a range of speeds depending on the concentration of CD4 and co-receptors on cell surfaces (53). This may influence the activity of fusion inhibitors across cell lineages and between individuals. Enfuvirtide was similarly active in vitro against CCR5, CXCR4, and dual tropic viruses according to some reports (1,32,45), whereas others showed higher IC50 values for CCR5 compared with CXCR4 using viruses, suggesting that patients with more advanced disease, harboring CXCR4 isolates, may experience a more potent response to enfuvirtide (10, 22, 23).

               Another aspect, which may affect the antiviral activity of enfuvirtide other than the evolution of drug resistance discussed below, includes the relative affinity of the specific virus gp120 for the chemokine receptor. Initial reports suggest that viruses with higher affinity may spend less time in the transition state where gp41 is exposed for enfuvirtide binding (58).

               Enfuvirtide has no activity against HIV-2 (1).

 

MECHANISMS OF ACTION

               The mechanism of action of enfuvirtide is derived from its composition and design and is directly associated with the HIV-host cell infecting process. Enfuvirtide interferes with HIV-1 entry into cells by inhibiting fusion of viral and cellular membranes. In order to understand how this drug works, it is important to briefly review the mechanisms of viral binding, fusion and entry into cells.

               The HIV-1 envelope glycoprotein consists of 2 non-covalently associated sub-units, gp120 – a surface subunit, and gp41 – a transmembrane subunit, which are presented on the lipid bilayer membrane of the virus. In common with other viruses, gp41 contains a short region within its sequence called the 'fusion peptide', which is required for mediating membrane fusion (26). The N terminal section of gp41 includes 2 highly conserved motifs, comprising of periodic repeats of leucine or isoleucine residues at every seventh position over eight helical turns, termed 'heptad-repeat' or 'leucine zipper' regions (20,31). These amino acid sequences termed HR1 and HR2, give the protein periodic hydrophobicity, and are predictive of an α-helical structure within gp41 (6, 8, 9).

               After the initial binding of the viral gp120 subunit to the host cell CD4 and chemokine co-receptors CCR5 and/or CXCR4 (13, 18, 21, 24, 28, 42), gp41 undergoes a change from a configuration where its fusion peptide is pointed inward toward the viral surface, to one where the fusion peptide is sprung outward toward the cell membrane, similar to the mechanism described for influenza virus (5). In this extended gp41 conformation, the intertwined N-terminal HR1 and C-terminal HR2 regions collapse together to form a thermodynamically stable 6-helix configuration, that provides the energy necessary for pulling the viral and cell membranes into close proximity, which leads to membrane fusion (29,44). This is a critical step in the viral life cycle, leading to the penetration of the viral core into the cytoplasm and cell infection (10,41).

               By corresponding to C-terminal amino-acid residues of the HR2 domain of gp41 (69), enfuvirtide blocks this gp41 change in configuration by mimicking the HR2 domain and binding competitively to the HR1 domain when gp41 is in its extended conformation thus blocking HR1-HR2 fusion (41, 60). This in turn inhibits virus-cell membrane approximation and subsequent fusion and viral entry into target cells (Figure 1).

 

MECHANISMS OF RESISTANCE

               Drug resistance is the viral defense mechanism against attempts to suppress its replication, and has been a major obstacle to the success of HIV-1 antiretroviral therapy. Despite a growing arsenal of drugs and the development of potent regimens, a significant amount of patients develop drug resistance and fail therapy. The addition of a new class of drugs – the entry inhibitors – of which enfuvirtide is the first, enlarges our drug arsenal, however does not provide a protecting shield against the development of drug resistance to this drug class as well.

               Drug resistance arises from mutations in the viral genome, specifically in the regions that encode the molecular targets of therapy. Viruses that carry or develop mutations that confer drug resistance are selected for and eventually become the predominate population. In HIV RT and protease these mutations alter the viral enzymes in such a way that their function is no longer or less inhibited by the drug, improving viral replication. An understanding of the genetic changes that render a particular drug ineffective is important to the development of new drugs, to designing the optimal drug combinations, and potentially also for the clinical management of individual patients. The same mechanism is thought to occur in gp41 inhibitors.

               In persons who have not been exposed to enfuvirtide, small studies have reported very little variance in the HR1 domain (amino acids 36-45) in HIV-1 B and non-B subtypes (37, 61, 70, 71). A somewhat larger variance was seen in areas outside this region, the relevance of which needs to be determined (57, 65).

               In vitro studies including virus passages in increasing concentrations of drug as well as phenotypic analyses of site-directed mutants defined a highly conserved 3-amino acid motif, (glycine, isoleucine, valine – GIV, positions 36-38), within the HR1 region of gp41 as critical for the loss of susceptibility to enfuvirtide. Serine replacing glycine at position 36 (G36S) and methionine replacing valine at position 38 (V38M) were particularly noted as important, supporting the proposed association of the 2 heptad regions of gp41 (60). Similar analyses have recently extended these observations to the whole HR1 region (52).

               Initial in-vivo studies in the enfuvirtide Phase I trial demonstrated the rapid emergence (within 14 days) of resistance to enfuvirtide, and demonstrated selection for additional mutations (67). In subsequent Phase II trials viral load (VL) patterns after enfuvirtide monotherapy showing an initial decline followed by a gradual return toward baseline values by the end of the 28-day treatment period (39), suggested the development of resistance, emphasizing the limitations of simply adding enfuvirtide (or any new agent) to an already failing regimen (10). Point mutations in the regions of the fusion protein binding site within gp41 were detected in ~50% of the patients treated with higher enfuvirtide doses in these trials (40).

               In the Phase III enfuvirtide trials, 94% of patients with protocol-defined virologic failure had virus with amino-acid substitutions at the enfuvirtide binding HR1 domain of gp41, associated with a wide range of decreases (by a factor of 5 to 401) in phenotypic susceptibility to enfuvirtide (35). Further subgroup analyses found that following enfuvirtide therapy, persons with viral isolates which were more resistant to RT and protease inhibitors had a greater decrease in susceptibility to enfuvirtide, suggesting that the antiviral activity of enfuvirtide is preserved when combined with additional active agents in the regimen (62).

Methods to Overcome or Prevent Resistance

               Monotherapy of antiretroviral drugs leads to the evolution of drug resistance and rapid therapy failure, and enfuvirtide is no exception to that rule, as has been discussed above. Similarly to other infecting agents, the best way to decrease the emergence of drug-resistant virus seems to be the simultaneous administration of several agents that interfere with different stages of the virus life cycle. The data on drug resistance from enfuvirtide studies are just now being released, and early reports support this hypothesis. It has been seen that persons with virus isolates with increased resistance to RT and protease inhibitors, have a greater reduction in susceptibility to enfuvirtide (62). This sheds light on the optimal timing to add enfuvirtide to a failing drug regimen, and further data need to be accumulated in order to help define the patient population that would best benefit from this drug and the optimal timing for its administration, that would also prevent the evolution of resistance.

 

PHARMACOKINETICS

               Enfuvirtide has been administered as a single or multiple-dose SC injection with pharmacokinetic studies conducted to determine key parameters such as Cmax, AUC, Tmax, half-life and apparent clearance. These studies have been completed in healthy and in HIV-infected persons (1).

Absorption

               In HIV-infected subjects, a single dose of 90 mg SC injection resulted in a Cmax of 4.59 ± 1.5 µg/ml (median Tmax – 8 hours) and an AUC of 55.8 ± 12.1 µg•h/ml. The absolute bioavailability was 84.3% ± 15.5%. When administered as 90 mg twice daily to HIV-infected subjects, steady-state pharmacokinetics yielded, Cmax of 5.0 ± 1.7 µg/ml (median Tmax – 4 hours), Cmin of 3.3 ± 1.6 µg/ml and AUC of 48.7 ± 19.1 µg•h/ml.

Distribution

               At steady state the volume of distribution was 5.5 ± 1.1 L after a 90 mg SC dose. When examined over a range from 2 to10 µg/ml, enfuvirtide was 92% bound to plasma proteins, primarily albumin with a lower extent of binding to alpha-1 acid glycoprotein.

Routes of Elimination

               Although mass balance studies have not been completed in humans, the catabolism of enfuvirtide is anticipated to proceed via amino acid breakdown and recycling. However, experiments with human microsomes and hepatocytes indicate that enfuvirtide is hydrolyzed to a deamidated metabolite (M3). The M3 metabolite has been measured in plasma following enfuvirtide administration with an AUC of 2.4% to 15% of the enfuvirtide AUC (1). After a single dose, the plasma half-life of enfuvirtide is 3.8 ± 0.6 hours. Apparent clearance has been determined after single dose (24.8 ± 4.1 mL/h/kg) and twice daily dosing (30.6 ± 10.6 mL/h/kg).

 

DOSAGE

Adults and children

               Enfuvirtide is a 36-amino acid peptide and oral treatment with it is not feasible. Intravenous and continuous SC infusion have been attempted, however abandoned (39, 40). The recommended dose of enfuvirtide in adults is 90 mg (1 ml) twice daily, injected subcutaneously into the upper arm, anterior thigh or abdomen. Each injection should be given at a site different from the preceding injection site, and only where there is no current injection site reaction from an earlier dose (1, 41).

               Clinical studies of enfuvirtide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

               In children 4 through 16 years old, the recommended dosage of enfuvirtide is 2 mg/kg twice daily up to a maximum dose of 90 mg twice daily, and specific guidelines based on body weight are available (1). No data are available yet to establish a dose recommendation of enfuvirtide in pediatric patients below the age of 4 years.

Renal Failure

               There is no recommended dosage in patients with renal failure, as formal pharmacokinetic studies of enfuvirtide have not been conducted in patients with renal insufficiency. However, analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is not affected in patients with creatinine clearance greater than 35 ml/min. The effect of creatinine clearance less than 35 ml/min on enfuvirtide clearance is unknown (1).

Hepatic Failure

               Formal pharmacokinetic studies on enfuvirtide have not been conducted in patients with hepatic impairment.

Body Composition

               Data from enfuvirtide clinical trials indicate that females have a plasma clearance that is 20% lower than males after adjusting for body weight. Enfuvirtide clearance decreases with body weight and relative to a 70 kg male, a 40 kg male is expected to have a 20% lower clearance and a 40 kg female a 36% lower clearance (1).

Ascites/Edema

               Formal pharmacokinetic studies on enfuvirtide have not been conducted in patients with ascites/edema.

Chronic Diarrhea/Malabsorption

               No recommended dosage in patients with chronic diarrhea/malabsorption, however because enfuvirtide is administered subcutaneously no dosage changes are anticipated.

Malnutrition

               As mentioned above, lower body weight results in a lower enfuvirtide clearance, but no dosage changes are recommended.

Pregnancy

               Enfuvirtide is classified in category B for pregnant women, as animal studies revealed no evidence of harm to the fetus from its use. However, there are no adequate and well-controlled studies in pregnant women, and this drug should be used during pregnancy only if clearly needed. To monitor maternal-fetal outcomes of pregnant women exposed to enfuvirtide and other antiretroviral drugs, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

               It is not known whether enfuvirtide is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving enfuvirtide (1).

 

ADVERSE EFFECTS

               Enfuvirtide is currently given as a small volume, SC injection. In all studies up to date, the most common adverse effect of enfuvirtide administration has been localized injection site reactions, which are typically mild but occur in the majority (98%) of patients. Most patients had their first reaction during week 1, with no evidence of an increase in the severity of injection-site reactions over time (50, 51).

               Frequent symptoms of injection-site reactions included erythema (87%), induration (84%), and nodules and cysts (82%). Other symptoms included edema and hemorrhage. Among persons who had pain or discomfort from injection-site reactions, most had either mild tenderness (50%) or moderate pain without limitation of usual activities (42%). Nine percent had pain or discomfort requiring non-topical analgesic agents or limiting usual activities, and none required hospitalization.

               Only small percentages of patients (3%) discontinued treatment with enfuvirtide because of injection-site reactions. Research continues into ways of minimizing local injection-site reactions and ways of managing them more effectively.

               In addition to local injection-site reactions, in the combined Phase-3 trials safety results, 78% of patients in the enfuvirtide group and 75% in the control group had had an adverse event that was related to the treatment regimen. Diarrhea, nausea, and fatigue were the most frequently reported treatment-related adverse events in both groups. Peripheral neuropathy and decreased appetite were the only treatment-related adverse events that occurred with a frequency at least 5 percent higher in the enfuvirtide group than in the control group.

               Overall, 22 patients in the enfuvirtide group (7%) and 8 patients in the control group (5 %) had adverse events with onset before week 24 that led to withdrawal from the study. The most frequent adverse events leading to withdrawal were vomiting and nausea (1% in the enfuvirtide group and 1% in the control group for both).

               Persons in the enfuvirtide group had a higher rate of pneumonia compared to patients in the control group (50 patients-6% vs.1 patient-0.3%). It is unclear if the increased incidence of pneumonia is related to enfuvirtide use, however, because of this finding, patients with HIV infection should be carefully monitored for signs and symptoms of pneumonia, especially if they have underlying conditions which may predispose them to pneumonia, such as low initial CD4 cell counts, high initial VL levels, intravenous drug use, smoking, and a prior history of lung disease (1). Sepsis also occurred more frequently in the combined enfuvirtide group (2% vs. 1%), but the exposure-adjusted rates were not significantly different.

               Hypersensitivity reactions that may recur with re-challenge have been associated with enfuvirtide therapy. These reactions included individually and in combination: rash, fever, nausea and vomiting, chills, rigors, hypotension, and elevated serum liver transaminases. Other adverse events that may be immune mediated and have been reported in subjects receiving enfuvirtide include primary immune complex reaction, respiratory distress, glomerulonephritis, and Guillain-Barre syndrome. Risk factors that may predict the occurrence or severity of hypersensitivity to enfuvirtide have not been identified (1).

               Treatment-related eosinophilia (>700 cells/ml) occurred in a greater proportion of patients in the enfuvirtide group (11% vs. 2%). Review of the cases of individual patients with eosinophilia did not reveal any clinical events suggestive of systemic hypersensitivity (1).

               There were five deaths during the Phase 3 enfuvirtide studies, all of which were related to the progression of HIV disease and were not considered to be attributable to enfuvirtide administration.

               Overall, studies report that the degree of satisfaction of patients receiving SC enfuvirtide is good (14, 15). Enfuvirtide had little impact on activities of daily living and most patients stated that they would choose to continue with the drug, and that the need to deliver it via twice-daily SC injections was not considered an important barrier. Patients surveyed found the injections were 'easy' or 'very easy' to self-administer in 67% of cases, and found aspects of drug storage (81%), medication preparation (71%), and needle and vial disposal (94%) also 'easy' or 'very easy'.

Overdoses

               There are no reports of human experience of acute overdose with enfuvirtide. The highest dose administered to humans in a clinical trial was SC 180 mg as a single dose. There is no specific antidote for overdose with enfuvirtide, and treatment of overdose should consist of general supportive measures (1).

 

MONITORING REQUIREMENTS

Therapeutic Drug Monitoring

               There are no data on therapeutic drug monitoring of enfuvirtide.

Other Laboratory Monitoring

               Enfuvirtide does not appear to interfere with intracellular pathways and is therefore expected to be associated with fewer metabolic complications than existing treatments (12). Clinically meaningful changes in laboratory parameters in persons receiving enfuvirtide, which are potentially related to it, are rare and include leukopenia, anemia, increased amylase level, hyperlipidemia and elevated liver enzymes (50, 51).

 

DRUG INTERACTIONS

               In an in vitro human microsomal study, enfuvirtide at 90 mg twice daily did not inhibit CYP450 enzymes. In an in vivo human metabolism study enfuvirtide did not alter the metabolism of CYP3A4, CYP2D6, CYP1A2, CYP2C19 or CYP2E1 substrates (1).

               Enfuvirtide is indicated for use in HIV infected persons in combination with highly active antiretroviral therapy (HAART) regimens, which commonly include drugs that are substrates, inhibitors and/or inducers of cytochrome P450 isozymes. Furthermore, many HIV-1 infected persons have co-infections and concurrent diseases requiring the concomitant use of additional drugs. In pharmacokinetic interaction studies, no clinically relevant drug-drug interactions occurred when enfuvirtide was co-administered with ritonavir, ritonavir/saquinavir or rifampin, confirming the low potential for metabolic drug-drug interactions involving enfuvirtide (1, 3).

               Enfuvirtide exhibited additive to synergistic in vitro effects when combined with individual members of various antiretroviral classes, including zidovudine, lamivudine, nelfinavir, indinavir, and efavirenz (1, 2, 63).

               The fusion process may occur at a range of speeds depending on the concentration of CD4 and co-receptors on cell surfaces. This may influence the activity of fusion inhibitors across cell lineages and between individuals. Inhibitors of co-receptors, another class of entry inhibitors, slow the fusion process, hence are highly synergic with fusion inhibitors, providing an insight into potential future combination therapies (53, 55, 64).

 

CLINICAL INDICATIONS

               Enfuvirtide is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy (1).

               In adults, preliminary Phase I and II studies in persons receiving enfuvirtide set the optimal dosing and administration parameters (90 mg twice daily in a SC injection). These studies demonstrated potent dose-related immunological and virological responses, without clinically significant short-term toxic effects, demonstrating that drugs with this mechanism of action are feasible options for treating HIV-1 infected persons failing current antiretroviral therapy (Table 1) (39, 40, 47, 49).

               The 24-week results of two parallel pivotal Phase III studies of enfuvirtide (TORO 1 and TORO 2), in patients with extensive previous treatment, have recently been reported (Table 1). One (50) involved 491 HIV-infected subjects in North-America and Brazil and the other (51) involved 504 HIV-infected subjects in Europe and Australia. These were randomized open-label studies, and all participants were treatment experienced and/or had documented resistance to each of the 3 classes of currently available RT and protease inhibitors. Upon study entry subjects received optimized background regimens (using genotypic and phenotypic testing), and then were randomly assigned to receive or not to receive 90 mg of enfuvirtide twice daily.

               At week 24, the combined mean reductions in viral load (1.55 log10 copies/ml in enfuvirtide recipients compared with 0.71 log10 copies/ml in the controls) and increases in CD4 (71 cells/ml in enfuvirtide recipients compared with 35 cells/ml in the controls) statistically significantly favored the enfuvirtide recipients. The percentage of patients with protocol-defined virologic failure was much lower in the enfuvirtide groups than in the control groups (46% vs. 71%). However, only 20% of patients who received enfuvirtide achieved a VL of less than 50 copies/ml after 24 weeks of therapy. The durability of response is unknown, as is any effect on progression of clinical disease (30).

               This chapter is written when only the initial clinical trials on enfuvirtide have been performed, and it must be remembered that studies performed for registration purposes may not reflect the final pattern of use of an antiretroviral agent (53). Encouraging earlier initiation of enfuvirtide as part of a 'first salvage' as opposed to a 'deep salvage' regimen may prove to be more beneficial for patients. At that point, the exact time of which remains to be determined, virus isolates may be less resistant and cross-resistant, and the use of more active drugs may increase viral suppression. Indeed, in the two TORO studies, the greatest response to therapy was seen in patients whose optimized background regimens included effective antiretroviral drugs (19).

               Enfuvirtide will likely be used as the 'anchor' drug in salvage therapy regimens for patients who have failed several conventional combination therapies or have been infected with drug-resistant virus. Further studies are needed to better define its role in other patient populations, including those with double-class experience, pediatric patients, prevention of mother-to-child-transmission and prevention of HIV transmission to healthcare workers (10).

               Studies evaluating the use of enfuvirtide in children (4-16 years) have also been reported, although in smaller numbers (Table 2). At adjusted doses, safety, tolerability and potency were similar to those seen in adults, and additional studies are ongoing (12, 16, 27).

T-1249

               T-1249 is a second-generation compound that mimics the HR2 gp41 domain, similarly to enfuvirtide, and is the second fusion inhibitor to be evaluated in a Phase I/II trial. This peptide consists of 39 amino acids and begins two heptad repeats N-terminal to the start of enfuvirtide (44). This incorporates HR2 residues that bind to the deep hydrophobic pocket (cavity) at the distal end of HR1, which is thought to stabilize the interaction between HR2 and HR1 peptides (33). It is considerably more difficult to select viruses resistant to a peptide that contains the cavity-binding region compared to one that doesn't (60). This implies that high-affinity ligands targeting the highly conserved coiled coil, and particularly the cavity, will have broad-spectrum anti-HIV-1 activity with a reduced propensity to develop resistance (4, 7).

               The clinical trials of T-1249 are at early stages, about 3 years behind enfuvirtide. Initial results show that T-1249 is well tolerated, has pharmacokinetic characteristics that support once daily dosing, and confers potent, dose-related suppression of plasma VL (36). T-1249 appears to be active against most of the enfuvirtide-resistant viruses (34, 53), and resistant isolates which reduce sensitivity to enfuvirtide by a mean of 88 fold, reduce susceptibility to T-1249 by only 3.3 fold (34).

 

Tables and Figures

Table 1. Clinical Studies Involving Enfuvirtide Administration In HIV-1 Infected Adults

Table 2. Clinical Studies Involving Enfuvirtide Administration in HIV-1 Infected Children

Figure 1. Proposed mechanism of T-20 action. (Reprinted with permission of Nature Publishing Group, Nature Medicine, Vol. 4, Issue 11, 1998, by J. Michael Kilby, et al.)

 

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