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

Lalezari, Jacob Pa; Eron, Joseph Jb; Carlson, Margritc; Cohen, Calvind; DeJesus, Edwine; Arduino, Roberto Cf; Gallant, Joel Eg; Volberding, Paulh; Murphy, Robert Li; Valentine, Fredj; Nelson, Emily Lk; Sista, Prakash Rk; Dusek, Alexk; Kilby, J Michaell

Clinical Science

Objectives: 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.

Methods: 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.

Results: The mean baseline plasma HIV-RNA level was 4.81 log10 copies/ml and the mean CD4 cell count was 134.8 cells/μl. 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 log10 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 log10 decline from baseline. The mean gain in absolute CD4 cell counts at 48 weeks was 84.9 cells/μl. Trough plasma concentrations of enfuvirtide were consistently higher than target concentrations.

Conclusion: 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.

From the aQuest Clinical Research, San Francisco, CA, USA; bUniversity of North Carolina, Chapel Hill, Durham, NC, USA; cCenter for Clinical AIDS Research and Education, University of California, Los Angeles, CA, USA; dCommunity Research Initiative New England, Brookline, MA, USA; eIDC Research Initiative, Altamonte Springs, FL, USA; fUniversity of Texas Health Science Center, Houston, TX, USA; gDivision of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA; hUniversity of California and the San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; iDivision of Infectious Diseases, Northwestern University, Chicago, IL, USA; jAIDS Clinical Trials Unit and Center for AIDS Research, New York University School of Medicine, New York, NY, USA; kTrimeris Inc., Durham, NC, USA; and lUAB HIV Outpatient Clinic, University of Alabama, Birmingham, AL, USA.

Correspondence to: Jacob Lalezari, Quest Clinical Research, 2300 Sutter Street, Suite 202, San Francisco, CA 94115, USA. E-mail:

Received: 24 June 2002; revised: 7 November 2002; accepted: 12 November 2002.

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Over the past few years a dramatic improvement in the morbidity and mortality of HIV-infected individuals has been reported [1,2]. However, in a large proportion of patients, the available antiretroviral therapies fail to suppress viral replication [3–5], and these numbers are predicted to rise still further [6]. One of the main reasons for treatment failure is the development of drug-resistant HIV variants. Future treatment options for patients experiencing virological rebound are generally limited, but can be optimized by basing the selection of new regimens on a genotypic or phenotypic drug resistance profile of plasma virus [7].

The 16 antiretroviral agents currently available for the treatment of HIV all belong to one of only two mechanistic classes: reverse transcriptase inhibitors (RTI) and protease inhibitors. Viral isolates from heavily pretreated patients often possess multiple mutations of the HIV reverse transcriptase and protease genes, resulting in multi-drug resistance and few or no further therapeutic options [8]. New pharmacological agents effective at alternative points in the viral replication cycle would make valuable additions to the anti-HIV armamentarium [9], particularly with respect to expanding therapeutic options for the growing number of treatment-experienced patients [10].

After HIV surface glycoprotein (gp120) binds to CD4 cell receptors, along with a chemokine co-receptor (CXCR4 or CCR5; both expressed on lymphocytes and mononuclear cells) [11], the transmembrane glycoprotein gp41 undergoes conformational changes that facilitate the fusion of cellular and viral membranes [12]. Blocking this conformational change inhibits virus–cell membrane fusion and subsequent entry into target cells. Synthetic peptides that mimic critical amino acid sequences, which promote the correct folding of gp41 into its secondary structure, have been shown to block cell-to-cell transmission and viral replication in vitro [13].

One of these synthetic compounds is enfuvirtide, a 36 amino acid peptide previously known as T-20. The primary sequence of enfuvirtide was derived from a naturally occurring motif (amino acid residues 638–673) within the HR2 domain of the HIV-1HXB2 gp41 transmembrane glycoprotein. In vitro, enfuvirtide exhibits potent and selective inhibition of de-novo infection in cell-to-cell virus transmission by binding to a critical region of gp41, thereby preventing virus–host cell membrane fusion [14]. This mode of action is demonstrated by the correlation between reduced HIV-1 susceptibility to enfuvirtide and the emergence of mutations in the ectodomain of gp41 that reduce drug binding, shown to develop under enfuvirtide selective pressure in vitro [15] and in vivo [16]. This novel mechanism therefore results in a lack of cross-resistance to enfuvirtide for viral isolates resistant to one or more of the current drug classes, and offers an alternative therapeutic strategy. Additional potential targets for new treatment approaches include the two distinct steps involved in HIV entry into cells that occur before virus–cell membrane fusion, i.e. gp120–CD4 cell binding and chemokine co-receptor binding.

When administered intravenously, enfuvirtide monotherapy resulted in dose-related plasma viral load suppression over 14 days [17], providing proof-of-concept that therapies aimed at blocking cell entry could provide potent and clinically significant suppression of viral replication. However, intravenous administration is impractical, and relatively small peptides such as enfuvirtide are generally not orally bioavailable. Therefore, current clinical trials are investigating the safety and efficacy of subcutaneous administration. A 28-day dose-ranging study showed dose-related, potent antiretroviral activity of subcutaneous enfuvirtide [18]. Doses of 50 mg a day or more resulted in viral load changes that are comparable with previously studied antiretroviral drugs given as monotherapy [19–23]. To date, a case report from a single patient only has described the long-term subcutaneous administration of enfuvirtide, and this resulted in prolonged suppression (> 16 weeks) of plasma viremia [24]. Therefore, to address the question of the longer-term safety and feasibility of subcutaneous enfuvirtide in a combination treatment regimen, we designed a rollover study (T20-205) among patients with extensive previous treatment experience.

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HIV-infected adults who had previously been enrolled in short-term enfuvirtide studies, and who had no enfuvirtide-related drug toxicities that resulted in study discontinuation, were eligible to participate in this rollover study. There were no enfuvirtide-naive patients in the study. Details of patients’ previous antiretroviral therapy is provided in Table 1.

Patients were required to have a Karnofsky performance score of 60 or greater and hematology and chemistry laboratory results within predefined limits [hemoglobin ≥ 8 g/dl (no transfusions within 30 days before entry); platelets ≥ 75 000/μl; total bilirubin ≤ 2.0 mg/dl; serum glutamic-oxaloacetic transaminase ≤ 5.0 × upper limit of normal (ULN); serum glutamate-pyruvate transaminase ≤ 5.0 × ULN; creatinine ≤ 2.0 × ULN; neutrophils ≥ 800 cells/μl]. There were no restrictions on absolute CD4 cell counts or on previous treatment with approved therapies. Patients also needed to have the ability to self-administer enfuvirtide and the willingness to give written informed consent.

Patients were ineligible for enrollment if they had evidence of active opportunistic infections or serious neoplastic conditions, chronic diarrhea, coagulation disorders, or were currently receiving immune modulators or other investigational treatments.

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Design and statistical considerations: open-label trial

This study design enabled enfuvirtide-experienced patients to receive a longer duration (48 weeks) of treatment in combination with an individualized antiretroviral regimen. On screening, blood obtained for safety assessments and for viral genotypic resistance testing allowed investigators to select individualized concomitant antiretroviral regimens consisting of at least two or more new or recycled agents for each patient. Patients who qualified for the trial then received 50 mg (45 mg deliverable) enfuvirtide every 12 h by subcutaneous self-administration in combination with conventional agents. During the study, subjects were allowed to change concomitant antiretroviral drugs for the management of toxicity.

The primary objective of study T20-205 was to determine the safety of prolonged subcutaneous enfuvirtide self-administration in combination with other antiretroviral agents. Secondary objectives included an evaluation of enfuvirtide plasma pharmacokinetics, antiviral efficacy and immunological response. The mean and maximum changes from baseline in log10 plasma HIV RNA and in absolute CD4 cell counts were summarized for the intent-to-treat (ITT) population and analysed using a paired t-test. If the assumptions for the paired t-test were unfulfilled, the Wilcoxon signed rank test was used as an appropriate non-parametric alternative. On-treatment analyses (OT) were conducted for change from baseline in log10 plasma HIV-1 RNA and CD4 cell count. In these analyses patients with data at each visit week were included in the calculation of the summary statistics (missing data were not imputed). ITT (missing = failure) and OT analyses of the percentage of patients with less than 400 copies/ml and more than 1 log reduction were conducted. In the former, the denominator is the number of patients enrolled (n = 71) and in the latter it is the number of patients with evaluable data at the visit week of interest.

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Clinical and laboratory monitoring

Adverse events, tolerability and toxicity assessments were based on physical examinations, vital signs and laboratory testing (including urinalysis, blood analysis, hepatic profiles, coagulation assays and complete blood counts). The severity of adverse events was graded according to the AIDS Clinical Trials Group toxicity grading scale [25]. Local injection site reactions were quantified according to a predetermined grading scale, adapted from the AIDS Vaccine Evaluation Group Grading of Severity of Adult Adverse Experiences, and classified as either mild, moderate or severe. Enfuvirtide plasma concentrations were determined as previously described [17], using a sandwich-capture enzyme-linked immunosorbent assay. Pre-dose plasma concentrations of enfuvirtide were obtained from all patients at each scheduled clinic visit, and a pharmacokinetic assessment was performed over the dosing interval on day 28, with blood samples taken at hours 0, 0.5, 1, 2, 4, 6, 8 and 12. Trough enfuvirtide plasma concentrations were determined on day 14 and at weeks 8, 12, 16, 20, 24, 32, 40 and 48. HIV-RNA levels were monitored using the Roche Amplicor assay (Roche, Inc., Somerville, NJ, USA), which has a lower limit of quantitation (LOQ) of 400 copies/ml. The Roche UltraSensitive assay (50 copies/ml LOQ) was used for samples with viral loads of less than 400 copies/ml. Absolute and percentage CD4 cell counts were calculated using standard flow cytometry methods.

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All 71 patients entering the rollover study had previously participated in clinical studies of enfuvirtide (TRI-001, n = 6; TRI-002, n = 1; TRI-003, n = 64). The mean time elapsed between studies for TRI-001 patients was 763 days, 24 days for the TRI-002 patient, and 125 days for the TRI-003 patients. One patient withdrew before receiving enfuvirtide; therefore, the ITT population consisted of 70 patients. Demographic data and patient disposition are summarized in Table 1.

Forty-six patients (out of the ITT population) were taking background antiretroviral drugs the day before dosing with enfuvirtide. Patients had been exposed to a median of nine previous antiretroviral drugs. Seventy patients (98.6%) had previous nucleoside RTI therapy, 69 (97.2%) had protease inhibitor experience and 56 (78.9%) had previously received non-nucleoside RTI. The median number of drugs combined with enfuvirtide in T20-205 was five per patient (range 3.0–12.0). Most patients made at least one change to the background regimen during the protocol. The reasons for changing were not recorded.

Adherence to enfuvirtide was assessed using patient diaries and by counting the returned vials of medication. By the estimation of returned vials, 84.1% of patients were at least 90% compliant to week 48.

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Safety and tolerability

A total of 1064 treatment-emergent events were reported by 70 of the ITT patient set (100.0%), the majority of which (925 events; 86.9%) were grade 2 or less in severity. Just under 50% of patients experienced diarrhea and 44% reported experiencing nausea. Hyperlipidemia and neuropathy were reported in 25 and 10% of patients, respectively. Approximately 19% of patients developed rash and approximately 7% reported a general allergic reaction. No rash or allergic reaction was defined by an investigator as a hypersensitivity reaction.

In total, 266 events (25.0%) were considered by the study investigator to be treatment related. The most common treatment-related adverse events were associated with the injection of enfuvirtide, with 52 patients (74.3%) experiencing at least one injection site-related adverse event (injection site reactions, 47.1%; site mass, 32.9%; site pain, 27.1%; site inflammation, 15.7%; injection site hemorrhage, 7.1%; and injection site edema, 5.7%). No patients discontinued treatment as a result of injection site reactions. Treatment-related diarrhea was experienced by eight patients (11.4%), and nausea and asthenia by six patients each (8.6%). Other than injection site reactions, no specific adverse events could be attributed directly to enfurvirtide. Another phase II study (T20-206) and phase III studies of enfuvirtide will include a control arm enabling the discrimination of enfuvirtide-related adverse events. Treatment-related adverse events occurring in 5% or more of the patients are listed in Table 2.

Of the 266 treatment-related adverse events, most (236, 88.7%) were classified as grade 1 or grade 2. Such events were reported by 58 (82.9%) and 26 patients (37.1%), respectively. Injection site reaction was the most common treatment-related grade 1 event reported (31 patients, 44.3%). Grade 1 injection site mass was reported by 21 patients (30.0%). Grade 1 injection site pain and injection site inflammation were reported by 16 (22.9%) and 11 patients (15.7%), respectively. Grade 2 asthenia, injection site pain, diarrhea and insomnia were each reported by three patients (4.3%). Grade 3 hyperlipemia was reported by four patients (5.7%), and a grade 4 γ-glutamyl transpeptidase increase was reported by four patients (5.7%). All other events judged as grade 2, 3 or 4 were reported by either one (1.4%) or two patients (2.9%).

Forty-four serious adverse events were reported and 10 of these, reported by seven patients (10.0%), were considered in the opinion of the investigator to be potentially related to enfuvirtide (leukopenia, anemia, increased amylase level, elevated γ-glutamyl transpeptidase, elevated serum transaminase levels and abnormal thinking). Similarly to adverse events in general, there was no clustering or pattern to the serious adverse events.

Clinically meaningful changes in laboratory parameters were rare, with only two patients (2.9%) demonstrating treatment-related increases in amylase and transaminases and four patients (5.7%) demonstrating elevated γ-glutamyl transpeptidase. Several abnormal laboratory results were reported as serious, as listed above. There were no other meaningful changes in clinical chemistry, hematology or urinalysis results. Treatment-related adverse events of anemia, leukopenia, hematuria, and increased serum glutamate-pyruvate transaminase were reported by one (1.4%) patient each during the study. Treatment-related increased amylase and increased serum glutamic-oxaloacetic transaminase were reported by two patients (2.9%) each. Elevated γ-glutamyl transpeptidase was reported by four patients (5.7%).

There were five deaths during the study, all of which were related to the progression of HIV disease and were not considered to be attributable to enfuvirtide administration. One patient (1017) enrolled in clinical trial T20-205 died as a result of the progression of disease during the study. Patient 1043 died as a result of soft tissue carcinoma. Three patients discontinued from study participation because of adverse events that resulted in death shortly after their discontinuation. Patient 1028 discontinued because of Aspergillus pneumonia, resulting in respiratory failure and death. Patient 1056 discontinued because of pneumonia that resulted in death, and patient 1051 discontinued because of the worsening complications of progressive multifocal leukoencephalopathy that also resulted in death. All of these events were considered to be unrelated to enfuvirtide.

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Antiviral activity and immunological response

OT analysis demonstrated a mean decline of 1.33 log10 copies/ml within 14 days of enfuvirtide treatment initiation (Fig. 1a), which was maintained over the 48-week treatment period (P < 0.001) for the change from baseline at week 48. The mean response at week 48 was −1.35 log10 copies/ml (SE ± 0.22).

At baseline, three patients (4.3%) in the ITT population had a viral load below 400 copies/ml. At week 48, a total of 23 out of 70 patients (32.9% ITT analysis; 56% OT analysis; see Fig. 1b) had achieved a virological response greater than 1 log10 copies/ml from baseline or to below 400 copies/ml. Of these, nine patients (12.9% of the ITT population) were less than 50 copies/ml, seven (10%) were greater than 50 but less than 400 copies/ml, and the remaining seven patients achieved a reduction of more than 1 log10 but were above 400 copies/ml.

A total of 24 patients (34.3%) in the ITT population experienced virological failure (defined as two consecutive HIV-RNA levels within 0.5 log10 copies/ml of baseline after week 8). Fourteen of these patients were discontinued from the study, and the other 10 were allowed to remain on treatment because of continued evidence of immunological benefit and limited options for treatment alternatives. The genetic basis for virological failure will be examined in a separate analysis of the entire enfuvirtide phase II program.

The mean gain in absolute CD4 cell counts at 48 weeks was 84.9 cells/μl (OT analysis; P < 0.001 for change; Fig. 2). The median gain was 77.0 cells/μl (range −82.5 to 405.0 cells/μl).

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Enfuvirtide pharmacokinetics

The day 28 enfuvirtide plasma concentration data revealed an area under the curve (AUC) of 22611.6 ng.h/ml, a maximum concentration (Cmax) of 2569.6 ng/ml, a minimum concentration (Cmin) of 1129.8 ng/ml, and a time to maximum concentration (Tmax) of 4.0 h. Fig. 3 presents the mean plasma levels achieved in the 12 h after dose administration on day 28. At all timepoints during the 12 h evaluation period, the plasma enfuvirtide concentration was greater than 1000 ng/ml.

The mean trough plasma concentration associated with 50 mg (45 mg deliverable) enfuvirtide twice-daily subcutaneous self-administration was greater than 1000 ng/ml at all clinic visits over the 48-week study period (data not shown).

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In this study, 70 heavily pretreated patients received an optimized background antiretroviral regimen in addition to enfuvirtide. The design did not include a control group for comparison, and therefore only inferences regarding safety and regimen efficacy can be drawn. Furthermore, patients were permitted to make changes to their background regimen during the course of the study for reasons such as the management of potential drug-related toxicities, although viral load increases may have influenced these changes. Therefore, therapeutic changes made partly in response to a rising viral load may have contributed to regimen durability over the 48 weeks of the study. However, several important observations can be made from the results to 48 weeks of treatment with enfuvirtide with an optimized background.

The safety profile of enfuvirtide administered chronically in an advanced population is particularly important and relevant. Injection site reactions were the most frequently reported adverse events. Injection site induration, pain and general reactions were reported by 30–50% of patients, but were usually mild in severity. No patient discontinued treatment because of an injection site reaction or an inability to continue receiving drug by subcutaneous injection, indicating that injection site reactions were not treatment limiting. Despite a small proportion of patients reporting severe adverse events, there was no firm evidence to suggest that these were attributable to enfuvirtide. Such a correlation should form the focus of future controlled studies.

Over 90% of patients were at least 75% compliant, and 30% of patients were 100% compliant throughout 48 weeks. Furthermore, in a sub-study involving patients enrolled on the T20-205 study, it was reported that after 48 weeks of treatment with subcutaneously administered enfuvirtide there was little effect on the activities of daily living [26].

In this advanced population with extensive antiretroviral experience [mean baseline antiretroviral exposure 9.5 drugs (± 0.36), baseline viral load > 4.81 log10 (± 0.11) copies/ml] efficacy at 48 weeks suggests that a potent, durable suppression of HIV is achievable with enfuvirtide-containing regimens. Twenty-three patients (32.9%) in the ITT population achieved significant suppression at week 48, with either a greater than 1.0 log10 decline from baseline viral load or less than 400 copies/ml HIV RNA. In the OT population, viral suppression (< 400 copies/ml or > 1.0 log decline) was sustained successfully in 56% throughout one year of therapy. These results compare favorably with the results obtained in antiretroviral-experienced patients on other triple-class treatment regimens [22].

Encouragingly, trough plasma levels of enfuvirtide (> 1000 ng/ml) exceeded the geometric mean EC50 (12 ng/ml) of the baseline virus isolates from this trial. In addition, an increase in CD4 lymphocytes with a concomitant decrease in HIV-RNA plasma levels was observed over the course of the trial period. The data presented here support the hypothesis that enfuvirtide has activity in patients who are triple-class experienced.

These results emphasize the concept that agents directed against novel, highly conserved processes associated with viral entry confer potent suppression of HIV replication. Ongoing phase III multicenter, randomized controlled trials will assess the contribution of enfuvirtide as a component of multi-drug salvage therapy in extensively pretreated patients.

A variety of other agents directed against viral entry are now in preclinical development [27]. Synergy between enfuvirtide and inhibitors of CXCR4 or CCR5 co-receptor interactions has been observed in vitro [28,29]. The utilization of multiple agents, targeted at distinct steps of the viral entry process (CD4 cell binding, co-receptor binding and envelope fusion), is likely to yield potent suppression of viral replication. Such a treatment regime may prove to be especially important in treating patient populations exhibiting multi-drug resistance to the existing classes of antiretroviral agents that exert their effects intracellularly.

Potential conflicts of interest: Jacob P. Lalezari receives research support from Trimeris and Roche; Joseph J. Eron is an ad hoc consultant to Trimeris and receives research support through the University of North Carolina from Trimeris and Roche; Calvin Cohen has previously received research support and speaker honoraria from Roche and Trimeris; Edwin DeJesus serves as an advisory board member for Roche; Paul Volberding has previously served as an advisory board member for Roche; Robert L. Murphy is a consultant for Trimeris and Roche; Fred Valentine is an intermittent member of the Trimeris clinical advisory board; Emily L. Nelson, Prakash R. Sista and Alex Dusek are employees of the study sponsor; and J. Michael Kilby receives research support through UAB from Trimeris and Roche, and has received speaker honoraria from Roche.

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Antiretroviral therapy; enfuvirtide; fusion inhibitor; T-20

© 2003 Lippincott Williams & Wilkins, Inc.