 |
 |
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
15 June 1996 | Volume 124 Issue 12 | Pages 1019-1030
Objective: To study the addition of a third human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, nevirapine, to the combination of zidovudine and didanosine.
Design: A 48-week, randomized, double-blind, placebo-controlled trial at 16 AIDS (acquired immunodeficiency syndrome) Clinical Trials Units.
Patients: 398 adults who had HIV-1 infection, had 350 or fewer CD4+ T lymphocytes/mm3, and had had more than 6 months of previous nucleoside therapy.
Intervention: 1) Either nevirapine or placebo [200 mg/d for 2 weeks, then 400 mg/d thereafter] and 2) open-label zidovudine (600 mg/d) and didanosine (400 mg/d for patients weighing more than equals to 60 kg).
Measurements: CD4+ T lymphocyte counts, time to first HIV-1 disease progression event or death, adverse events, and nevirapine levels in plasma samples taken at random were measured in all patients. Plasma levels of HIV-1 RNA; HIV-1 infectivity titer in peripheral blood mononuclear cells; serum p24 antigen levels; and plasma levels of zidovudine and didanosine were measured in patients enrolled at half the study sites.
Results: After 48 weeks of study treatment, the patients assigned to the triple-combination regimen (nevirapine, zidovudine, and didanosine) had an 18% higher mean absolute CD4 cell count (95% CI, 7% to 29%; P = 0.001), a 0.32 log10 lower mean infectious HIV-1 titer in peripheral blood mononuclear cells (CI, 0.05 to 0.59 log10 infectious units per million cells; P = 0.023), and a 0.25 log10 lower mean plasma HIV-1 RNA level (CI, 0.03 to 0.48 log10RNA copies/mL; P = 0.028) than did patients assigned to the double-combination regimen (zidovudine and didanosine). Severe rashes were more common among patients assigned to receive the triple combination (9% compared with 2%; P = 0.002). Risk for disease progression did not differ between the two groups (relative hazard of the triple-combination group, 1.24 [CI, 0.75 to 2.06]; P > 0.2), although the study had only moderate power to detect a major difference.
Conclusions: Adding nevirapine to zidovudine and didanosine improved the long-term immunologic and virologic effects of therapy and was associated with severe rash among the patients studied, who had had extensive previous therapy. These results support 1) the continuing development of combinations of more than two antiretroviral drugs to increase and prolong HIV-1 suppression and 2) the potential utility of nevirapine in combination regimens.
Author and Article Information
The National Institute of Allergy
ARTICLE
Nevirapine, Zidovudine, and Didanosine Compared with Zidovudine and Didanosine in Patients with HIV-1 Infection
A Randomized, Double-Blind, Placebo-Controlled Trial
Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators*
For author affiliations and current author addresses, see end of text.
*For a listing of additional members of the AIDS Clinical Trials Group Protocol 241 Investigators, see the Appendix.
Acknowledgments: The authors thank the patients and staff who contributed to the study and thank Xiao-Jian Zhou, PhD (University of Alabama at Birmingham, Birmingham, Alabama) for the pharmacology analysis, Elaine Gebhardt (AIDS Clinical Trials Group Statistical and Data Analysis Center), the participating AIDS Clinical Trials Group Unit site virologists and virology laboratory staff, and the AIDS Clinical Trials Group Operations Office staff.
Grant Support: In part by the AIDS Clinical Trials Group of NIAID. Zidovudine was provided by Glaxo Wellcome, Research Triangle Park, North Carolina; didanosine was provided by Bristol-Myers Squibb, Wallingford, Connecticut; and nevirapine was provided by Boehringer-Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
Requests for Reprints: Richard T. D'Aquila, MD, Infectious Disease Unit, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129.
Current Author Addresses: Dr. D'Aquila: Infectious Disease Unit, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, MA 02129.
This article has been cited by other articles:
|
|
 |
|
  T.-C. Chou Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies Pharmacol. Rev., September 1, 2006; 58(3): 621 - 681. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Palmer, V. Boltz, N. Martinson, F. Maldarelli, G. Gray, J. McIntyre, J. Mellors, L. Morris, and J. Coffin Persistence of nevirapine-resistant HIV-1 in women after single-dose nevirapine therapy for prevention of maternal-to-fetal HIV-1 transmission PNAS, May 2, 2006; 103(18): 7094 - 7099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Brogly, P. Williams, G. R. Seage III, J. M. Oleske, R. Van Dyke, K. McIntosh, and for the PACTG 219C Team Antiretroviral Treatment in Pediatric HIV Infection in the United States: From Clinical Trials to Clinical Practice JAMA, May 11, 2005; 293(18): 2213 - 2220. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Van Herrewege, G. Vanham, J. Michiels, K. Fransen, L. Kestens, K. Andries, P. Janssen, and P. Lewi A Series of Diaryltriazines and Diarylpyrimidines Are Highly Potent Nonnucleoside Reverse Transcriptase Inhibitors with Possible Applications as Microbicides Antimicrob. Agents Chemother., October 1, 2004; 48(10): 3684 - 3689. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yazdanpanah, D. Sissoko, M. Egger, Y. Mouton, M. Zwahlen, and G. Chene Clinical efficacy of antiretroviral combination therapy based on protease inhibitors or non-nucleoside analogue reverse transcriptase inhibitors: indirect comparison of controlled trials BMJ, January 31, 2004; 328(7434): 249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C R Palmer Ethics, data-dependent designs, and the strategy of clinical trials: time to start learning-as-we-go? Statistical Methods in Medical Research, October 1, 2002; 11(5): 381 - 402. [Abstract] [PDF]
|
|
|
|
|
|
R. W. King, R. M. Klabe, C. D. Reid, and S. K. Erickson-Viitanen Potency of Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) Used in Combination with Other Human Immunodeficiency Virus NNRTIs, NRTIs, or Protease Inhibitors Antimicrob. Agents Chemother., June 1, 2002; 46(6): 1640 - 1646. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J Olivieri Nevirapine + efavirenz based salvage therapy in heavily pretreated HIV infected patients Sex Transm Inf, February 1, 2002; 78 (1): 72 - 73. [Full Text] [PDF]
|
|
|
|
|
|
G. M Raab and T. Parpia Random effects models for HIV marker data: practical approaches with currently available software Statistical Methods in Medical Research, April 1, 2001; 10(2): 101 - 116. [Abstract] [PDF]
|
|
|
|
|
|
V. Joly, M. Moroni, E. Concia, A. Lazzarin, B. Hirschel, J. Jost, F. Chiodo, Z. Bentwich, W. C. Love, D. A. Hawkins, et al. Delavirdine in Combination with Zidovudine in Treatment of Human Immunodeficiency Virus Type 1-Infected Patients: Evaluation of Efficacy and Emergence of Viral Resistance in a Randomized, Comparative Phase III Trial Antimicrob. Agents Chemother., November 1, 2000; 44(11): 3155 - 3157. [Abstract] [Full Text]
|
|
|
|
|
|
L. T. Bacheler, E. D. Anton, P. Kudish, D. Baker, J. Bunville, K. Krakowski, L. Bolling, M. Aujay, X. V. Wang, D. Ellis, et al. Human Immunodeficiency Virus Type 1 Mutations Selected in Patients Failing Efavirenz Combination Therapy Antimicrob. Agents Chemother., September 1, 2000; 44(9): 2475 - 2484. [Abstract] [Full Text]
|
|
|
|
 |
|
 G. J. Hanna, V. A. Johnson, D. R. Kuritzkes, D. D. Richman, J. Martinez-Picado, L. Sutton, J. D. Hazelwood, and R. T. D'Aquila Comparison of Sequencing by Hybridization and Cycle Sequencing for Genotyping of Human Immunodeficiency Virus Type 1 Reverse Transcriptase J. Clin. Microbiol., July 1, 2000; 38(7): 2715 - 2721. [Abstract] [Full Text]
|
|
|
|
|
|
X.-J. Zhou, L. B. Sheiner, R. T. D'Aquila, M. D. Hughes, M. S. Hirsch, M. A. Fischl, V. A. Johnson, M. Myers, J.-P. Sommadossi, and The National Institute of Allergy and Infectious D Population Pharmacokinetics of Nevirapine, Zidovudine, and Didanosine in Human Immunodeficiency Virus-Infected Patients Antimicrob. Agents Chemother., January 1, 1999; 43(1): 121 - 128. [Abstract] [Full Text]
|
|
|
|
 |
|
 D. K. Owens, M. L. Brandeau, and C. H. Sox Effect of Relapse to High-Risk Behavior on the Costs and Benefits of a Program to Screen Women for Human Immunodeficiency Virus Interfaces, May 1, 1998; 28(3): 52 - 74. [Abstract] [PDF]
|
|
|
|
 |
|
 F. J. Palella, K. M. Delaney, A. C. Moorman, M. O. Loveless, J. Fuhrer, G. A. Satten, D. J. Aschman, S. D. Holmberg, and The HIV Outpatient Study Investigators Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection N. Engl. J. Med., March 26, 1998; 338(13): 853 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. G. Montaner, P. Reiss, D. Cooper, S. Vella, M. Harris, B. Conway, M. A. Wainberg, D. Smith, P. Robinson, D. Hall, et al. A Randomized, Double-blind Trial Comparing Combinations of Nevirapine, Didanosine, and Zidovudine for HIV-Infected Patients: The INCAS Trial JAMA, March 25, 1998; 279(12): 930 - 937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Gulick HIV Treatment Strategies: Planning for the Long Term JAMA, March 25, 1998; 279(12): 957 - 959. [Full Text] [PDF]
|
|
|
|
 |
|
 Nonnucleoside Reverse Transcriptase Inhibitors AIDS Clinical Care, October 1, 1997; 1997(1001): 1 - 1. [Full Text]
|
|
|
|
 |
|
 Major advances in the treatment of HIV-1 infection DTB, April 1, 1997; 35(4): 25 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Cohn Recent advances: hiv infection–I BMJ, February 15, 1997; 314(7079): 487 - 487. [Full Text]
|
|
|
|
|
|
S. M. Hammer, D. A. Katzenstein, M. D. Hughes, H. Gundacker, R. T. Schooley, R. H. Haubrich, W. K. Henry, M. M. Lederman, J. P. Phair, M. Niu, et al. A Trial Comparing Nucleoside Monotherapy with Combination Therapy in HIV-Infected Adults with CD4 Cell Counts from 200 to 500 per Cubic Millimeter N. Engl. J. Med., October 10, 1996; 335(15): 1081 - 1090. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Nevirapine Potentiates AZT-ddI Combination AIDS Clinical Care, August 1, 1996; 1996(801): 6 - 6. [Full Text]
|
|
|
|
 |
|
 Triple Antiretroviral Therapy for HIV Journal Watch Dermatology, August 1, 1996; 1996(801): 16 - 16. [Full Text]
|
|
|
|
 |
|
 TRIPLE ANTIRETROVIRAL THERAPY FOR HIV Journal Watch (General), July 5, 1996; 1996(705): 3 - 3. [Full Text]
|
|
Article
