Enfuvirtide, an HIV-1 Fusion Inhibitor, for Drug-Resistant HIV Infection in Nort(100md.com)

Enfuvirtide, an HIV-1 Fusion Inhibitor, for Drug-Resistant HIV Infection in Nort

http://www.100md.com

     An additional updated safety analysis combined data from the two phase 3 studies (TORO 1 and TORO 2). This combination offered a larger population on which to base a characterization of the safety profile of enfuvirtide and was appropriate because the studies have similar designs, criteria for patient selection, and protocol-specified analyses. For this update, a separate analysis investigated the incidence of combinations of adverse events that might be considered clinically equivalent in order to identify whether small increases in the incidence of several adverse events would, when combined, show a relevant difference between treatment groups.

    Statistical Analysis

    Data on efficacy were analyzed for an intention-to-treat population, defined as all patients who underwent randomization, received at least one dose of study medication, and had at least one plasma HIV-1 RNA measurement after treatment began. HIV-1 RNA values obtained after confirmed virologic failure were excluded from the analysis. Missing values were imputed for the analysis with the use of a last-observation-carried-forward method. The log10 HIV-1 RNA value at week 24 was defined as the mean of the last two log10 HIV-1 RNA values on completion of 24 weeks in the study, the mean of the two HIV-1 RNA values that confirmed virologic failure, or for patients who withdrew from the study, the mean of the last two log10 HIV-1 RNA values before withdrawal. Changes from base line to week 24 in log10 HIV-1 RNA levels and CD4+ cell counts were evaluated by analysis of covariance including terms for the randomization stratum (of plasma HIV-1 RNA level and use or nonuse of newly approved or investigational agents), the treatment group, and the interaction between stratum and treatment group, with the base-line phenotypic sensitivity score (for the evaluation of the change in the HIV-1 RNA level) or the base-line CD4+ cell count (for the evaluation of the change in the CD4+ cell count) as covariates.

    To test the robustness of the results of the primary efficacy analysis based on the last-observation-carried-forward method of imputation, three sensitivity analyses were performed as follows: the change from base line in viral load was set at zero for patients who withdrew before week 24; the change from base line in viral load was set at zero for patients who withdrew or who had virologic failure before week 24; and in a cohort analysis, separate analyses were performed without the use of the last-observation-carried-forward method for patients who completed 4, 8, 12, 16, 20, and 24 weeks of treatment.

    For analysis of categories of virologic response (with patients who had missing data or virologic failure treated as having had no response), a stratified Mantel–Haenszel test was used. Time to virologic failure was estimated by the Kaplan–Meier method. A stratified log-rank test was used to compare the time-to-event curves of the two treatment groups.

    Results

    Study Population

    A total of 501 patients underwent randomization at 48 centers in the United States, Canada, Mexico, and Brazil between December 2000 and June 2001. Of these patients, 491 (326 in the enfuvirtide group and 165 in the control group) used the study medication at least once, had a follow-up visit to record safety-related data, and had an assessment of the HIV-1 RNA level after

Demographic and Base-Line Characteristics of the Patients

Demographic and base-line characteristics were similar in the two groups (Table 1). The genotypic sensitivity scores at base line (mean, 1.9 in each group) and the phenotypic sensitivity scores at base line (mean, 1.7 in the enfuvirtide group and 1.8 in the control group) indicated that HIV-1 from the majority of patients in each group was sensitive to less than two of the drugs used in the background regimen. Previous treatment with at least five protease inhibitors was reported for a slightly higher percentage of patients in the enfuvirtide group (49.4 percent) than in the control group (39.4 percent, P=0.04). The percentage of patients who had previously received lopinavir–ritonavir, classified as a newly approved or investigational antiretroviral drug in this study, was also higher in the enfuvirtide group (38.7 percent) than in the control group (27.9 percent, P=0.02). In both groups, there was a mean of four drugs in the background regimen (Table 1).

    Changes in Treatment and Premature Withdrawal

    In the control group, 106 patients (64.2 percent) had protocol-defined virologic failure by week 24, and 81 of these patients switched to enfuvirtide (Figure 1). By week 24, 37 patients in the enfuvirtide group (11.3 percent), 18 patients remaining in the control group (21.4 percent), and 6 of the patients who had switched to enfuvirtide (7.4 percent) had withdrawn from the study.

    Adherence

    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.

    Efficacy

    Changes in the Plasma HIV-1 RNA Level

    The least-squares mean change from base line in the plasma HIV-1 RNA level was a decrease of 0.764 log10 copies per milliliter in the control group and a decrease of 1.696 log10 copies per milliliter in the enfuvirtide group, representing a difference between groups of 0.933 log10 copies per milliliter (P<0.001) (Table 2). The least-squares mean differences significantly favored the enfuvirtide group in all four randomization strata (P<0.05 for all comparisons). The sensitivity analyses yielded least-squares mean differences of 0.888 log10 copies per milliliter (P<0.001) when the change from base line in viral load was set at zero for patients who withdrew from the study and 0.802 log10 copies per milliliter (P<0.001) when the change from base line in viral load was set at zero for both patients who withdrew and those who had virologic failure. The least-squares mean difference also remained significant (P<0.05) in each of the cohort analyses performed at time points up to week 24. At week 24, the proportion of patients in each category of response was significantly greater in the enfuvirtide group than in the control group

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.

    Changes in CD4+ Cell Counts

    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 (Table 2).

    Safety

    Injection-Site Reactions

    At week 24, nearly all patients in the enfuvirtide group (98.2 percent) had had at least one injection-site reaction, with most having their first reaction during week 1. Among patients who had pain or discomfort from injection-site reactions, most had either mild tenderness (49.7 percent) or moderate pain without limitation of usual activities (41.7 percent); 8.7 percent had pain or discomfort requiring nontopical analgesic agents or limiting usual activities, and none required hospitalization. Frequent symptoms of injection-site reactions included erythema (in 87.1 percent of patients), induration (in 84.0 percent), and nodules and cysts (in 81.6 percent). There was no evidence of an increase in the severity of injection-site reactions over time. Only small percentages of patients (2.8 percent in the enfuvirtide group and 1.2 percent in the group that switched to enfuvirtide) discontinued treatment with enfuvirtide because of injection-site reactions.

    Adverse Events at Week 24

    Because of the 2:1 ratio for randomization, the design of the study allowing patients in the control group to switch to enfuvirtide, and the lower rate of virologic failure in the enfuvirtide group after 24 weeks of treatment, the total number of patient-years of exposure to the randomly assigned treatment regimen was approximately 2.5 times as high in the enfuvirtide group (162.8 patient-years) as in the control group (64.9 patient-years). After 24 weeks, 77.6 percent of patients in the enfuvirtide group and 74.5 percent in the control group had had an adverse event (excluding injection-site reactions) that was related to the treatment regimen. Diarrhea, nausea, and fatigue were the most frequently reported treatment-related adverse events in both groups (Table 3). 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 (6.7 percent) and 8 patients in the control group (4.8 percent) 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 in both groups (in 1.2 percent of patients in the enfuvirtide group and 1.2 percent of those in the control group), nausea in both groups (in 0.9 percent of patients in the enfuvirtide group and 1.2 percent of those in the control group), and diarrhea in the control group (1.2 percent). All other adverse events leading to withdrawal occurred in 0.6 percent of patients or less. Two patients who switched to enfuvirtide (2.5 percent) had adverse events that began after the switch and subsequently led to withdrawal from the study; these events were diarrhea in one patient and progression of the acquired immunodeficiency syndrome in the other patient. Similar percentages of patients in the two groups died (1.2 percent [four patients] in the enfuvirtide group and 2.4 percent [four patients] in the control group) or had a serious adverse event while receiving the treatment to which they were originally assigned (25.8 percent in the enfuvirtide group and 21.2 percent in the control group).