Rejoinder
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0092-8615/98 Copyright 0 1998 Drug Information Association Inc.
REJOINDER CHRISTY CHUANG-STEIN Director, Clinical Development Biostatistics I, Pharmacia & Upjohn Company, Kalamazoo, Michigan
RALPHDEMASI Senior Statistician, Department of Clinical Statistics, Glaxo Wellcome Inc., Research Triangle Park, North Carolina
This is a rejoinder to the preceding commentaries on the authors’ paper “Surrogate Endpoints in AIDS Drug Development: Current Status. ’’ The authors thank Drs. Ellenberg and Gould for their thought-provoking commentaries and reiterate that information accumulation in the AIDS area, including that from meta-analyses on the concordance between CD4 count and HIV-1 RNA response with the clinical response, is dynamic and fast paced. In addition, the authors remind the readers of the calculated risk associated with decision making in the drug development process. Some information that has become available since the writing of the original manuscript is also included. Key Words: AIDS; HIV- 1 ; Antiretroviral therapies; Surrogate endpoints
FIRST, THE AUTHORS would like to thank Drs. Ellenberg and Gould for their thoughtprovoking commentaries on their paper. Their comments and discussion pointed out the many challenges faced by clinicians, scientists, and pharmaceutical companies engaged in AIDS research. One such challenge is the pace with which hypotheses are formed and subsequently confirmedrefuted in this field. For example, there has been hope for a total blockage of the HIV-1 virus replication with potent threedrug combinations, only to find out later that virus continues to break through under such drug combinations. Perelson et al. speculated that if virus replication could be completely blocked by potent anti-retroviral drug combinations, it would take between 2-3 years of treatment to completely eradicate the virus
Reprint address: Christy Chuang-Stein, Director, Clinical Development Biostatistics 1, Pharmacia & Upjohn Company, 9162-227400, Kalamazoo. MI 49001.
from the infected host except for the proviral DNA that was incorporated into the infected CD4 cells (1). Even with researchers’ increased understanding of the processes and kinetics of HIV-1 replication in infected individuals, proving a complete blockage of virus replication in all tissue reservoirs remains a daunting task at the time this rejoinder was prepared. A recent report published in the January 1998 issue of Journal of Virology by van? Wout and colleagues (2) expressed some optimism that the HIV-1 reservoir in AIDS patients may be limited. They concluded that the absence of a large tissue reservoir for HIV-1 favors the possibility of completely eradicating HIV- 1. Undoubtedly, van’t Wout’s findings will be closely examined by other researchers and they will surely learn whether the expressed optimism will become a well-accepted fact. With all the uncertainty concerning total blockage of virus replication and the lack of empirical evidence regarding complete eradication at the moment, no one (the authors included) would
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