Enfuvirtide (T-20)

Updated April, 2011

 Philip A. Chan, MD, and  Rami Kantor, MD

 

               In the past three decades, antiretroviral therapy for HIV/AIDS has been designed to inhibit two key 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 (151, 160, 214), the durability of viral suppression is often limited. Contributing factors include poor penetration into protected sites containing a reservoir of HIV (109, 119), alterations in the bioavailability and metabolism of antiretroviral drugs (63), the need for adequate adherence to complex drug regimens (27, 43), drug toxicities, and the emergence of drug resistant viruses (179), resulting in multi-drug resistance and cross resistance with 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 agents from classes of antiretroviral drugs to which the patient has not previously been exposed are included in the regimen. In the past decade, novel therapies intended to inhibit HIV-1 entry into susceptible cells have been investigated (113), including interference with attachment of the virus to the cell, chemokine co-receptor interactions, and virus-cell membrane fusion (150).

               Enfuvirtide was the first entry inhibitor approved for clinical use by the FDA on March 13, 2003 (74), initiating a new class of treatment options for HIV infection (72, 49, 135, 139, 141, 203). This agent has been shown to provide benefit when given as part of a salvage regimen for persons with drug-resistant HIV-1, who have limited therapeutic options. In this chapter, we review current guidelines and recommendations related to enfuvirtide and summarize and update recent scientific data on this drug and post-approval clinical experience and research trends.

 

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 (82, 219)). This agent is produced synthetically in a process involving more than 100 steps (as compared with eight to 12 steps for a typical anti-HIV medication) to give a powder for subcutaneous injection (116). 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) (123).

Structure-Activity Relationship

               Based on the 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 therefore 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 (219), Wild et al. reported a 50% inhibitory concentration (IC50) of approximately 1.7 ng/ml. Since then, in-vitro activity of enfuvirtide has been 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) (82, 118).

               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 (150). 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 (82, 8, 91, 118), whereas others showed higher IC50 values for CCR5 compared with CXCR4 using viruses, suggesting that patients with more advanced disease or harboring CXCR4 isolates may experience a more potent response to enfuvirtide (26, 59, 60).

               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. Reports suggest that viruses with higher affinity may spend less time in the transition state where gp41 is exposed for enfuvirtide binding (177).

 

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 two non-covalently associated sub-units, the surface subunit gp120 and the transmembrane subunit gp41 which are present 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 (65). The N-terminal section of gp41 includes two highly conserved motifs, comprising of repeats of leucine or isoleucine residues at every seventh position over eight helical turns, termed ‘heptad-repeat’ or ‘leucine zipper’ regions (54, 83). These amino acid sequences termed HR1 and HR2 give the protein periodic hydrophobicity, and are predictive of an α-helical structure within gp41(22,23,25).

               After the initial binding of the viral gp120 subunit to the host cell CD4 and chemokine co-receptors CCR5 and/or CXCR4 (34, 46, 55, 62, 77, 114), 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 (20). 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, and leads to membrane fusion (78, 117). This is a critical step in the viral life cycle, leading to the penetration of the viral core into the cytoplasm and cell infection (26, 113).

               Similar to the C-terminal amino-acid residues of the HR2 domain of gp41 (220), 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 (113, 180). This in turn inhibits virus-cell membrane approximation and subsequent fusion and viral entry into target cells (Figure 1).

Video: Life Cycle of HIV

Video: Fusion and Cell Entry

Video: Fusion Inhibition

 

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 number of patients develop drug resistance and fail therapy. The addition of the entry inhibitor drugs, of which enfuvirtide is the first, increase our drug arsenal but does not provide a protective shield against the development of resistance to this 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 also for the clinical management of individual patients. The same mechanism is thought to occur in gp41 inhibitors.

               In-vitro studies including virus passages in increasing concentrations of drug and phenotypic analyses of site-directed mutants have defined a highly conserved three 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 two heptad regions of gp41 (180). Further studies have shown that mutations in the entire HR1 domain from position 36 to 45 confer resistance to enfuvirtide (143, 146, 190). In persons who have not been exposed to enfuvirtide, studies have reported very little variance in the HR1 domain in HIV-1 B and non-B subtypes (95, 182, 225, 229). These mutations do not seem to have an effect on the fitness of HIV replication in vivo (28). Other mutations or polymorphisms outside this region, such as A50V (11), may be associated with resistance to enfuvirtide, and testing to detect only the HR1 mutations may not be adequate for clinical management of suspected failure (110). The overall relevance of other mutations outside of the HR1 domain and association with resistance is unclear (168, 213).

               Initial in-vivo studies in the enfuvirtide phase I trial demonstrated the rapid emergence (within 14 days) of resistance to enfuvirtide, and selection for additional mutations (216). In subsequent phase II trials, viral load (VL) patterns after enfuvirtide monotherapy demonstrated an initial decline followed by a gradual return toward baseline values by the end of the 28-day treatment period (111), suggesting the development of resistance and emphasizing the limitations of simply adding enfuvirtide (or any new agent) to an already failing regimen (26). 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 (112).

               In 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 (positions 36 to 45), associated with a wide range of decreases (by a factor of five to 401) in phenotypic susceptibility to enfuvirtide (92, 143). 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 (189).

               Several enfuvirtide-induced mutations were related to changes in CD4 cell count, without a change in HIV-1 VL. Mutations V38A/E and N126K were associated with an increase in CD4 count and others including Q40H and L45M were associated with a CD4 decrease (3, 144). It is unknown why these mutations affect the CD4 cell count without a resulting change in VL, but it is hypothesized that complex viral and immune mediated mechanisms at the fusion site may promote or decrease viral entry leading to preservation or destruction of CD4 cells respectively, but have no effect on plasma VL.

               Post-marketing use of enfuvirtide has allowed accumulation of data on the development of drug resistance, confirming that enfuvirtide resistance mutations invariably occur in the HR1 domain of gp41(6, 28, 47, 138, 166) between positions 36 and 45. Mutations in HR1 outside of this motif (29, 205), as well as in other structural envelope domains (89, 196, 209) may also play a role in enfuvirtide resistance. Primary resistance mutations in the HR2 domain have not been well described (175). According to the Stanford HIV Sequence Database (hivdb.stanford.edu), enfuvirtide-associated mutations include G36D/E/V/S, I37V, V38E/A/M/G, Q40H, N42T, N43D/K/S, L44M, and L45M . The International AIDS Society (IAS-USA) reports similar resistance mutations, but does not include G36E/V, V38G, N43K/S, L44M, or L45M and does include Q39R (109). Other lists, such as the French National Agency for AIDS Research (ANRS, www.hivfrenchresistance.org) and REGA institute (regaweb.med.kuleuven.be), report similar mutations as IAS-USA and the Stanford Database. Some of these mutations have been confirmed in recent studies (18, 61), but due to the small number of individuals on enfuvirtide, it is difficult to accurately evaluate resistance associated mutations.

               Careful interpretation of enfuvirtide resistance is warranted, especially in globally prevalent HIV strains. The efficacy of enfuvirtide in non-subtype B HIV-1 is not well defined due to low overall use of enfuvirtide in HIV-infected populations in resource limited settings, where diverse subtypes predominate. Individuals who are naïve to enfuvirtide may have baseline resistance mutations in the HR1 domain which have been found across all studied subtypes (19, 61, 105, 128, 159, 165, 186). Prior, non-enfuvirtide ARV use may also select for enfuvirtide-related accessory resistance mutations (159). Non-subtype B strains may be susceptible to enfuvirtide (16, 58), however many demonstrate frequent polymorphisms at known subtype B resistance positions in the HR1 region and may have different resistance patterns to enfuvirtide (39, 71, 103, 200). Enfuvirtide is unlikely to have activity against HIV-2 or HIV-1 Group O (167, 221).

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 is the simultaneous administration of several agents that interfere with different stages of the virus life cycle. The data on drug resistance from enfuvirtide studies 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 (189). 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 subcutaneous 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 (82,149).

Absorption

               In HIV-infected subjects, a single dose of 90 mg subcutaneous 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 subcutaneous 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 α-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 deaminated 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 (82). 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 AND ADMINISTRATION

Adults and Children

               Enfuvirtide is a 36-amino acid peptide and oral treatment with it is not feasible. Intravenous and continuous subcutaneous infusions have been attempted, however abandoned (11, 112). Though studies have demonstrated equal efficacy of once-daily dosing regimens compared to twice-daily (92), they were underpowered to detect differences. The recommended dose of enfuvirtide in adults is therefore 90 mg (1 ml) twice daily, injected subcutaneously into the upper arm, anterior thigh or abdomen. Enfuvirtide has been studied as a once daily 180mg subcutaneous injection, but this is likely less effective and is not recommended (202). Other formulations have been tested, but are not approved for clinical use (218). 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 (82, 113).

               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 6 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 (82). No data are available yet to establish a dose recommendation of enfuvirtide in pediatric patients below the age of six 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, enfuvirtide appears to be minimally excreted by the kidneys and only 13% of the drug is cleared during hemodialysis (198). 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. Thus, no adjustment is recommended for patients with renal failure.

Hepatic Failure

               Enfuvirtide has minimal hepatic toxicity and may be safe in patients with liver disease or transplantation by minimizing direct toxicity and other drug interactions (199). 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 (82).

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 not recommended in pregnancy due to the lack of safety and clinical data (164). However, enfuvirtide is a class B drug and several small studies suggest that it is well tolerated in pregnancy with minimal placenta levels and no adverse effects (21, 81, 108, 133, 195). The risks and benefits of enfuvirtide administration in pregnancy should be assessed before administration and done in consultation with an expert in the field. 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 (82).

 

ADVERSE EFFECTS

               Enfuvirtide is currently given as a small volume, subcutaneous injection. In all studies 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 (10, 152, 123, 125). Most patients had their first reaction during the initial week, with no evidence of an increase in the severity of injection-site reactions over time (124, 125, 152, 208). Despite the limitation of subcutaneous injections, studies have suggested equal adherence in individuals receiving enfuvirtide versus other regimens ( 181) and that this method of administration may not lead to significant decreases in quality of life (17, 170). Alternative methods of administration, such as needle free systems (88, 120), use of smaller needles (187), or other devices (131) may be emerging options in patients experiencing injection site reactions (97, 131, 187).

               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. Enfuvirtide must be injected subcutaneously. It should not be administered intramuscularly or intravenously. Injection reactions can be minimized by varying the sites (abdomen, upper thighs, upper arm). Research continues into ways of minimizing local injection-site reactions and ways of managing them more effectively.

               In addition to local injection-site reactions, the combined phase III trials safety results showed 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 five percent higher in the enfuvirtide group than in the control group.

               Overall, 22 patients in the enfuvirtide group (7%) and eight 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 nausea and vomiting (1% in the enfuvirtide group and 1% in the control group, respectively).

               Pre-approval phase III trials had shown a slightly increased rate of bacterial pneumonia in patients in the treatment-arm of enfuvirtide (50 patients, 6% vs.1 patient, 0.3%) (82). However, follow-up studies have failed to find an increased risk (115). Recent case reports have suggested that enfuvirtide may be associated with occasionally severe staphylococcus aureus infections, although the correlation is unclear (56, 85). Sepsis also occurred more frequently in the combined enfuvirtide group (2% vs. 1%), but the exposure-adjusted rates were not significantly different. Other reported adverse events include localized amyloidosis (148) and/or granuloma formation (188).

               Hypersensitivity reactions that may recur with re-challenge have been associated with enfuvirtide therapy. These reactions have included rash, fever, nausea and vomiting, chills, rigors, hypotension, and/or elevated serum liver transaminases. It may be possible to desensitize patients to hypersensitivity reactions (68, 171). 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 Guillian-Barre syndrome. Risk factors that may predict the occurrence or severity of hypersensitivity to enfuvirtide have not been identified (82).

               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 (82).

               There were five deaths during the phase III enfuvirtide studies, all of which were related to the progression of HIV disease and were not considered to be attributable to enfuvirtide administration. Package inserts have been updated to include current efficacy and safety data (75).

               Overall, studies report that the degree of satisfaction of patients receiving subcutaneous enfuvirtide is good (36, 41). Education and counseling regarding the drug may improve quality of life (1) and should be performed before administration (104). 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 subcutaneous 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 subcutaneous 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 (82).

 

MONITORING REQUIREMENTS

Therapeutic Drug Monitoring

               Data on therapeutic drug monitoring of enfuvirtide are slowly emerging, demonstrating enfuvirtide levels lower and more variable than expected, necessitating further research (194).

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 (30). 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 (124, 125).

 

DRUG INTERACTIONS

               An in-vitro human microsomal study using enfuvirtide at 90 mg twice daily did not inhibit CYP450 enzymes. An in-vivo human metabolism study also did not alter the metabolism of enfuvirtide and CYP3A4, CYP2D6, CYP1A2, CYP2C19 or CYP2E1 substrates (82).

               Enfuvirtide is indicated for use in HIV-1 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 (13, 82).

               Enfuvirtide exhibited additive to synergistic in vitro effects when combined with individual members of various antiretroviral classes, including zidovudine, lamivudine, nelfinavir, indinavir, and efavirenz (7, 82, 206).

               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 (150, 153, 207, 211).

 

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 viral replication despite ongoing antiretroviral therapy (82).

               In adults, phase I and II studies in persons receiving enfuvirtide set the optimal dosing and administration parameters (90 mg twice daily in a subcutaneous injection). These studies demonstrated potent, dose-related immunologic and virologic response, without clinically significant short-term toxic effects, demonstrating that drugs with this mechanism of action are feasible options for treating HIV-1 infecting persons failing current antiretroviral therapy (111, 112, 122, 123). Subsequent clinical data demonstrate continued efficacy and safety(33, 64, 100, 156, 178) (Table 1). 

               According to current guidelines (57, 86, 73, 201) and consensus panels (172, 184), enfuvirtide is recommended as part of a multi-drug regimen for treatment experienced, HIV-1 infected individuals failing their current antiretroviral (ARV) medications. Enfuvirtide has not been studied in treatment-naïve individuals and, as with other ARVs, should never be used alone as drug resistance may develop rapidly (86, 132). Ideally, two and preferably three fully active ARV drugs from different classes should be used in the treatment of multi-drug resistant HIV-1. Current guidelines support the use of enfuvirtide in combination with NRTIs, NNRTIs, PIs, or other newer drugs such as raltegravir or maraviroc (52, 53, 137, 161). However, due to the complexity of subcutaneous enfuvirtide administration, the World Health Organization (WHO) guidelines do not mention the drug in its strategy for treatment of HIV in resource poor settings (223).

               Post-approval studies support the efficacy of enfuvirtide in combination with other ARVs in virologic suppression (10, 32, 50, 131, 173, 178, 183, 212), including in children (76, 222). Enfuvirtide may be associated with a better virologic response in combination with certain drugs, such as etravirine (137) and may lead to prolonged survival (5).

               Due to the toxicity and difficulty of enfuvirtide administration, several studies have evaluated switching from enfuvirtide to newer agents. Clinical trials indicate that changing from enfuvirtide to either raltegravir (48, 90, 96, 185, 197, 204) or etravirine (129) results in sustained virologic suppression with no adverse outcomes. Switching from enfuvirtide to another agent due to side-effects or for administration simplicity is also supported by current guidelines (57, 73) and is logical from a drug resistance aspect. When used in combination with other ARVs, enfuvirtide should not be stopped without starting another agent to maintain drug pressure; retrospective data suggest that this may lead to higher rates of virologic failure (67). Enfuvirtide does not appear to affect latent reservoirs of HIV-1 in combination with other ARVs (84). Anecdotally, recycling enfuvirtide, using the drug again as part of a different regimen in patients who had previously failed an enfuvirtide-containing regimen, was reported to have some benefit in a small, retrospective case study (38). This observation, requiring further investigation, was based on the rapid decline of enfuvirtide-associated resistance mutations when the drug was discontinued.

               There are several situations in which enfuvirtide may be beneficial if other treatment options are unavailable. In tuberculosis (TB)/HIV co-infection, enfuvirtide may represent a reasonable choice in salvage regimens because it has no interactions with first-line TB drugs rifampicin and rifabutin; other drugs such as PIs and NNRTIs may affect ARV drug levels (73). In patients who are experiencing side effects from ARVs, switching to an enfuvirtide-based regimen may reduce overall toxicity (193). Enfuvirtide has been shown to have minimal metabolic adverse effects and may be a reasonable alternative in patients for which this is a concern (37). The drug has low penetration across the blood brain barrier and, therefore, little to no drug levels accumulate in the cerebral spinal fluid (169, 210). This should be taken into account when treating patients with suspected neurologic manifestations of HIV-1 infection.

               Following enfuvirtide, newer molecules that inhibit gp41-mediated viral entry are in different stages of development. These include sifuvirtide (99, 215), P20 (228), C-34 (4, 155), SC29EK (154) and others (24, 98, 106, 158, 192). T-1249 was another entry inhibitor in development; however, trials were halted by the manufacturer due to formulation problems (70, 121, 140).. Sifuvirtide, administered by once daily subcutaneous injection, is similar to enfuvirtide and is in late phase II clinical trials (www.fusogen.com). Related HIV-1 entry inhibitors that block sites other than gp41 are also in development (79). Importantly, many of these entry inhibitors are still effective in HIV-1 strains that demonstrate resistance to enfuvirtide (40, 66, 99, 107, 121, 142, 154, 176), and may work in synergy (162, 163) by binding to different parts of the gp41. These data, though early and preliminary, suggest that these entry inhibitors may be beneficial in combination therapy and not simply replace enfuvirtide.

               In conclusion, enfuvirtide was the first HIV entry inhibitor approved for treatment of HIV-1 infected, treatment-experienced individuals failing ARV therapy as part of a multi-drug regimen. Enfuvirtide has shown significant durability and efficacy in combination with older as well as newer ARVs in virologic suppression of HIV-1. However, subcutaneous administration of enfuvirtide continues to limit its widespread use due to quality of life issues and injection site reactions. Newer entry inhibitors, currently in development, will hopefully be able to overcome these limitations and add to an important and effective ARV drug class.

 

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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