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Enfuvirtide, an HIV-1 Fusion Inhibitor
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New England Journal of Medicine; Volume 348:2175-2185; May 29, 2003; Number 22
In March, the Food and Drug Administration (FDA) approved enfuvirtide for patients who have had previous treatment for HIV-1 infection and who have evidence of viral replication despite ongoing antiretroviral therapy. In the current issue of NEJM 24-week efficacy and safety results were reported. Here is the data along with cogent excerpts for your perusal. 48-week data from these two studies are expected and will show the durability of what so far are good results for patients.
Enfuvirtide (previously known as T-20) is a synthetic 36-amino-acid peptide that binds to the first heptad-repeat region (HR1) of envelope glycoprotein 41 of human immunodeficiency virus type 1 (HIV-1), a protein that is critical
for the fusion of the virus with the cell membrane.7 In phase 1 and 2 clinical trials, enfuvirtide reduced the plasma viral load and was well tolerated when given as short-term monotherapy or as part of long-term combination therapy in patients who had previously been treated with multiple antiretroviral drugs.
TORO 1 Study of Enfuvirtide for Drug-Resistant HIV Infection in North and South America
ABSTRACT
Background; The T-20 vs. Optimized Regimen Only Study 1 (TORO 1) was a randomized, open-label, phase 3 study of enfuvirtide (T-20), a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor.
Methods; Patients from 48 sites in the United States, Canada, Mexico, and Brazil with at least six months of previous treatment with agents in three classes of antiretroviral drugs, resistance to drugs in these classes, or both, and with at least 5000 copies of HIV-1 RNA per milliliter of plasma were randomly assigned in a 2:1 ratio to receive enfuvirtide plus an optimized background regimen of three to five antiretroviral drugs or such a regimen alone (control group). The primary efficacy end point was the change in the plasma HIV-1 RNA level from base line to week 24.
Results; A total of 501 patients underwent randomization, and 491 received at least one dose of study drug and had at least one measurement of plasma HIV-1 RNA after treatment began. The two groups were balanced in terms of the median base-line HIV-1 RNA level (5.2 log10 copies per milliliter in both
groups), median CD4+ cell count (75.5 cells in the enfuvirtide group, and 87.0 cells in the control group), demographic characteristics, and previous antiretroviral therapy. At 24 weeks, the least-squares mean change from base line in the viral load (intention-to-treat, last observation carried forward) was a decrease of 1.696 log10 copies per milliliter in the enfuvirtide group, and a decrease of 0.764 log10 copies per milliliter in the control group (P<0.001). The mean increases in CD4+ cell count were 76 cells per cubic millimeter and 32 cells per cubic millimeter, respectively (P<0.001). Reactions at the site of the injections were reported by 98 percent of patients receiving enfuvirtide. There were more cases of pneumonia in the enfuvirtide group than in the control group.
Conclusions: The addition of enfuvirtide to an optimized antiretroviral regimen provided significant antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antiretroviral drugs and had multidrug-resistant HIV-1 infection.
A week-48 analysis will be performed in both trials to assess the durability
of the response to enfuvirtide. The introduction of enfuvirtide as the first of this new class of antiretroviral agent could make an important contribution to the successful, individualized treatment of growing numbers of patients who have limited remaining treatment options.
.... Injection-site reactions were the most common events associated with enfuvirtide treatment, occurring in most patients who received the drug, but pain or discomfort requiring analgesics or limiting usual activities occurred in only 8.7 percent. Only a small number of patients discontinued enfuvirtide therapy because of an injection-site reaction (2.8 percent of patients assigned to the enfuvirtide group and 1.2 percent of patients who switched to enfuvirtide). There was a high rate of adherence to enfuvirtide treatment, suggesting that injection-site reactions were not treatment-limiting.
... Overall, except for local injection-site reactions, the safety and tolerability of enfuvirtide in combination with an optimized background regimen were similar to those of the background regimen alone over the course of 24 weeks of therapy. ... pneumonia, primarily bacterial, occurred more frequently in the combined enfuvirtide group (50 patients [5.6 percent], or 4.9 per 100 patient-years) than in the control group (1 patient [0.3 percent], or 0.6 per 100 patient-years; P=0.02). Sepsis occurred more frequently in the combined enfuvirtide groupÉ.. Two patients had cases of systemic hypersensitivity reaction (both in TORO 1) that were considered to be related to enfuvirtide therapy, and both recurred on rechallenge..... Treatment-related eosinophilia (>700 cells per cubic millimeter) occurred in a greater proportion of patients in the enfuvirtide group..... Aside from eosinophilia, differences between the groups in the incidence of treatment-related grade 3 or grade 4 laboratory abnormalities were small, and no consistent pattern was evident to suggest a definitive association of enfuvirtide with any particular laboratory abnormality.
More Study details
Enfuvirtide (90 mg) was administered twice daily by subcutaneous injection into the abdomen, the upper arm, or the anterior aspect of the thigh. The first injection was administered by study personnel at the study site, and patients were trained in sterile technique and instructed in reconstituting and injecting enfuvirtide.
The optimized background (by resistance testing) regimen could include tenofovir, lopinavir-ritonavir, or both. Both of these agents were investigational at the start of the study but were approved in most countries during the course of the study. Ritonavir at doses of 266 mg per day or less (i.e., booster doses) was not counted as an active component in either a prestudy regimen or the background regimen. Changes in the background regimen were permitted only in the event of protocol-defined virologic failure or management of toxic effects. Adherence in both treatment groups was calculated with the use of a patient questionnaire that assessed the number
of missed doses of enfuvirtide or oral antiretroviral drugs during the four days preceding each study visit.
The mean level of adherence to the enfuvirtide component of the regimen over the 24-week period was at least 85 percent in 92.9 percent of patients. The overall adherence to the entire regimen in the enfuvirtide group was at least 85 percent in 88.0 percent of patients. The mean level of adherence to the background regimen in the control group was at least 85 percent in 90.3 percent of patients.
The percentage of patients with virologic failure by week 8 was greater in the control group (33.3 percent) than in the enfuvirtide group (16.0 percent), and this difference persisted to week 24 (control group, 64.2 percent; enfuvirtide group, 41.7 percent). The distribution of the time to virologic failure was significantly different between the two groups (P<0.001 by the log-rank test) (Figure 2). The median time to virologic failure was 99 days in the control group but could not be estimated in the enfuvirtide group.
At week 24, the increase from base line in the CD4+ cell count was significantly greater in the enfuvirtide group than in the control group.
Safety
The updated safety analysis included 663 patients in the enfuvirtide groups and 334 patients in the control groups from TORO 1 and TORO 2. At the time of the
updated analysis, 229 patients originally assigned to the control group had switched, adding enfuvirtide to their regimen. Because of the 2:1 ratio of randomization and the study design that allowed switching to enfuvirtide, patients in the original enfuvirtide group had 813 patient-years of exposure (median, 1.48 years per patient; range, <0.01 to 1.92) and patients in the control group had 163 patient-years of exposure (median, 0.35 year per patient; range, 0.04 to 1.60; ratio, 5:1). Patients exposed to enfuvirtide after switching had 214 patient-years of exposure (median, 1.08 years per patient; range, <0.01 to 1.71). Results were adjusted for exposure (presented in terms of the number of patients with an event per 100 patient-years of exposure), with all the patients exposed to enfuvirtide combined into one group (with a total of 1027 patient-years of exposure) and compared with the control group.
This update generally confirmed the safety profile seen at 24 weeks, with the following observations. Although the overall incidence of bacterial infections was similar in the two treatment groups after adjustment for exposure (183 patients in the combined enfuvirtide groups [20.5 percent], or 17.8 per 100 patient-years of exposure, and 30 patients in the control group [9.0 percent], or 18.4 per 100 patient-years of exposure; P=0.56), pneumonia, primarily bacterial, occurred more frequently in the combined enfuvirtide group (50 patients [5.6 percent], or 4.9 per 100 patient-years) than in the control group (1 patient [0.3 percent], or 0.6 per 100 patient-years; P=0.02). Sepsis occurred more frequently in the combined enfuvirtide group (16 patients [1.8 percent], or 1.6 per 100 patient-years, vs. 2 patients [0.6 percent], or 1.2 per 100 patient-years, in the control group), but the exposure-adjusted rates were not significantly different (P=0.37).
Two patients had cases of systemic hypersensitivity reaction (both in TORO 1) that were considered to be related to enfuvirtide therapy, and both recurred on rechallenge. In the first patient, who was taking enfuvirtide in combination with didanosine, stavudine, amprenavir, and ritonavir, rash, fever, and vomiting developed after eight days of treatment. On rechallenge on days 17 and 22 of the study, rash, fever, and vomiting recurred within hours after the administration of enfuvirtide. The eosinophil count increased progressively from 280 per cubic millimeter at base line (upper limit of normal, 570 per cubic millimeter) to 350 per cubic millimeter on day 12 of the study and 690 per cubic millimeter on day 15. Membranoproliferative glomerulonephritis developed in the second patient after 57 days of therapy with enfuvirtide in combination with tenofovir, lamivudine, lopinavir-ritonavir, amprenavir, and efavirenz. This patient had a history of diabetes, seasonal allergies, proteinuria, and hematuria. On rechallenge with all antiretroviral drugs on day 223, severe respiratory distress developed. No eosinophilia or increase from base line in the eosinophil count was noted.
Treatment-related eosinophilia (>700 cells per cubic millimeter) occurred in a greater proportion of patients in the enfuvirtide group (74 of 662 patients who could be evaluated [11.2 percent], or 11.5 patients per 100 patient-years) than in the control group (8 of 332 patients who could be evaluated [2.4 percent], or 4.9 patients per 100 patient-years). Eosinophilia was not associated with clinical events suggestive of systemic hypersensitivity.
Aside from eosinophilia, differences between the groups in the incidence of treatment-related grade 3 or grade 4 laboratory abnormalities were small, and no consistent pattern was evident to suggest a definitive association of enfuvirtide with any particular laboratory abnormality.
TORO 2 in Europe & Australia
ABSTRACT
Background: The T-20 vs. Optimized Regimen Only Study 2 (TORO 2) compared the efficacy and safety of 24 weeks of treatment with the fusion inhibitor enfuvirtide in combination with an optimized background antiretroviral regimen with the efficacy and safety of the optimized background regimen
alone.
Methods: The patients had previous treatment with each of the three classes of antiretroviral drugs, documented resistance to each class, or both and a plasma level of human immunodeficiency virus type 1 (HIV-1) RNA of at least 5000 copies per milliliter. They were randomly assigned in a 2:1 ratio to
receive either enfuvirtide (90 mg twice daily) plus a background regimen optimized with the aid of resistance testing (enfuvirtide group) or the background regimen alone (control group).
Results: Of the 512 patients who underwent randomization, 335 in the enfuvirtide group and 169 in the control group received at least one dose of study medication and had at least one follow-up measurement of plasma HIV-1 RNA. The median base-line plasma HIV-1 RNA level was 5.1 log10 copies per milliliter in both groups. The median CD4+ cell count was 98.0 cells per cubic millimeter in the enfuvirtide group and 101.5 cells per cubic millimeter in the control group. Patients had a median of seven years of previous treatment and had received a median of 12 antiretroviral drugs. The background regimen comprised a mean of four antiretroviral drugs in both groups. At 24 weeks, the
least-squares mean change from base line in the plasma viral load (intention-to-treat, last observation carried forward) was a decrease of 1.429 log10 copies per milliliter in the enfuvirtide group and a decrease of 0.648 log10 copies per milliliter in the control group, a difference of 0.781 log10 copies per milliliter (P<0.001). The mean increase in the CD4+ cell count was greater in the
enfuvirtide group (65.5 cells per cubic millimeter) than in the control group (38.0 cells per cubic millimeter, P=0.02).
Conclusions: The addition of enfuvirtide to an optimized background regimen provided significant viral suppression and immunologic benefit over a 24-week period in HIV-1-infected patients who had previously received multiple antiretroviral drugs.
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