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

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     Updated Safety Analysis

    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, 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.

    Discussion

    Our trial was designed specifically to evaluate a new class of anti–HIV-1 compounds in patients who have received treatment with multiple drugs. Resistance testing was used to construct an optimized background regimen for all patients in the trial. Along with the criteria for switching to enfuvirtide and the use of lopinavir–ritonavir and tenofovir, this approach allowed patients access to the best possible treatment options. This fact is reflected by the relatively high proportion of patients in the control group with responses to treatment despite the extensive resistance to antiretroviral drugs in this population of patients. This positive outcome was also due in part to the high level of adherence to treatment among patients in the control group ( 85 percent adherence in 90.3 percent of patients). The benefit of enfuvirtide was demonstrated by significant differences between the two treatment groups at week 24 in the magnitude of the reduction in the plasma HIV-1 RNA level, the proportion of patients in each category of virologic response, the distribution of time to virologic failure, and the increase in the CD4+ cell count.

    Although the last-observation-carried-forward method can overestimate the individual drug effect if the HIV-1 RNA level rebounds quickly after virologic failure, it was chosen to provide a consistent rule for handling patients in either group who discontinued treatment or had virologic failure, as well as for those who switched to enfuvirtide.18,19 The robustness of the primary result was confirmed by three stringent sensitivity analyses that clearly showed that the magnitude of the estimate of the effect of enfuvirtide treatment was not determined primarily by the method of imputation.

    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. The safety results obtained from the combined TORO 1 and TORO 2 studies after longer exposure to enfuvirtide showed a higher rate of pneumonia among patients receiving enfuvirtide than among patients in the control group, but the overall incidence of bacterial infection was similar in the two groups.

    Two patients had a hypersensitivity reaction that was considered to be related to enfuvirtide therapy and that recurred with rechallenge. There was a higher incidence of eosinophilia among patients receiving enfuvirtide, even after adjustment for the duration of exposure. Review of the cases of individual patients with eosinophilia did not reveal any clinical adverse events suggestive of hypersensitivity to enfuvirtide.

    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.

    In our study, enfuvirtide resulted in significant improvement in virologic and immunologic responses as compared with individualized, optimized, combination antiretroviral therapy alone. These findings are supported by the similar results obtained in the TORO 2 trial.15 These two studies provide firm proof of principle that HIV-1 glycoprotein 41 is a viable target for effective treatment of 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.

    Supported by Roche and Trimeris.

    Dr. Lalezari reports having received consulting and lecture fees from Roche and Trimeris. Dr. Henry reports having received consulting or lecture fees from Abbott, Agouron, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, and Merck and grant support from Bristol-Myers Squibb, GlaxoSmithKline, and Roche. Dr. Montaner reports having received consulting or lecture fees or grant support from Abbott, Agouron, Shire BioChem, Boehringer Ingelheim, Bristol-Myers Squibb, Dupont Pharma, Gilead Sciences, Glaxo Wellcome, Roche, Kucera Pharmaceutical, Merck Frosst, and Pharmacia & Upjohn. Dr. Piliero reports having received consulting and lecture fees from Roche Laboratories and grant support from Roche and Trimeris. Dr. Trottier reports having received consulting or lecture fees from Roche, Bristol-Myers Squibb, Agouron, and Abbott. Dr. Walmsley reports having received consulting or lecture fees from Abbott, Aguoron, Boehringer Ingelheim, Bristol-Myers Squibb, Dupont, GlaxoSmithKline, and Merck and grant support from Abbott, GlaxoSmithKline, and Boehringer Ingelheim. Dr. Cohen reports having received consulting fees, lecture fees, or grant support from Roche, Bristol-Myers Squibb, Abbott, Gilead, Boehringer Ingelheim, GlaxoSmithKline, and Trimeris. Dr. Kuritzkes reports having received consulting or lecture fees from Abbott, Bayer–Visible Genetics, Bristol-Myers Squibb, Gilead–Triangle, GlaxoSmithKline, Merck, Roche, Shire BioChem, Serono, Trimeris, Ortho Biotech, and ViroLogic and grant support from Roche, Trimeris, GlaxoSmithKline, Bristol-Myers Squibb, and Tanox. Dr. Eron reports having received consulting and lecture fees from Roche and grant support from Abbott, Merck, Roche, and Trimeris.

    We are indebted to the patient volunteers who took part in the trial.

    * Members of the TORO 1 (T-20 vs. Optimized Regimen Only Study 1) group are listed in the Appendix.

    Source Information

    From Quest Clinical Research, Mount Zion Hospital, and the University of California, San Francisco, San Francisco (J.P.L.); the HIV Program, Hennepin County Medical Center, Minneapolis (K.H.); the Oregon Health and Science University, Portland (M.O.); St. Paul’s Hospital and the University of British Columbia, Vancouver, Canada (J.S.G.M.); the Clinical Research Initiative, Albany Medical College, Albany, N.Y. (P.J.P.); the Clinique Médicale l’Actuel, Montreal (B.T.); the University of Toronto, Toronto (S.W.); the Community Research Initiative of New England, Boston (C.C.); the Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver (D.R.K.); the University of North Carolina at Chapel Hill School of Medicine, Chapel Hill (J.J.E.); Roche, Nutley, N.J. (J.C., L.D., M.S.); and Trimeris, Durham, N.C. (R.D., C.D., J.D.).

    This article was published at www.nejm.org on March 13, 2003.

    Address reprint requests to Dr. Lalezari at Quest Clinical Research, 2300 Sutter St., Suite 202, San Francisco, CA 94115, or at drjay@questclinical.com.

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