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However, in censoring patients who did not start antiretroviral therapy during follow-up, they have selectively eliminated from the deferred-therapy group, but not the early-therapy group, those patients in whom disease progression was relatively slow. This introduces potential bias when addressing the related question of when to initiate antiretroviral therapy for all patients with high CD4+ counts, for whom the timing of disease progression is unknown.
The number of patients eliminated from the analysis because of slower disease progression exceeds the numbers in each early-therapy group. As stated in the accompanying editorial,2 this study does not fully address the appropriate course of action for this sizable subgroup. Clinicians should take this information into account when counseling patients with high CD4+ counts about the appropriate timing for initiation of antiretroviral therapy.
Susan P. Buchbinder, M.D.
San Francisco Department of Public Health
San Francisco, CA
susan.buchbinder{at}sfdph.org
Vivek Jain, M.D.
University of California, San Francisco
San Francisco, CA
References
Specifically, patients who initiated antiretroviral therapy within 6 months after baseline and whose CD4+ count remained above 500 cells per cubic millimeter until initiation were included in the early group. Patients who either died untreated or who initiated antiretroviral therapy with a CD4+ cell count of more than 500 cells per cubic millimeter within 6 months after baseline were included in the deferred group. This implementation effectively places patients with a better prognosis in the early group, possibly resulting in an exaggeration of the estimated benefit of early initiation.
In addition to contributing to potential bias, this implementation has the effect of producing comparison groups that do not correspond to meaningful clinical strategies regarding the optimal CD4+ cell count at which to initiate antiretroviral therapy.
Miguel A. Hernán, M.D.
James M. Robins, M.D.
Harvard School of Public Health
Boston, MA
miguel_hernan{at}post.harvard.edu
References
In light of the conflicting data coming from both sides of the Atlantic, and a health care insurance system undergoing reform in the United States, we really do need the randomized clinical trial data before drawing any firm conclusions.1,2
Luc B. Gelinck, M.D.
Marchina E. van der Ende, M.D.
Erasmus Medical Center
Rotterdam, the Netherlands
l.gelinck{at}erasmusmc.nl
References
Jose R. Arribas, M.D.
Marta Mora, M.D.
Jose F. Pascual-Pareja, M.D.
Hospital La Paz
Madrid, Spain
jrarribas.hulp{at}salud.madrid.org
In response to Buchbinder and Jain: we note that patients whose CD4+ counts remain in the target window but who do not initiate therapy are not censored — they remain at risk of death in the analysis and are subject only to what we call outside-of-protocol censoring. However, if we eliminate this censoring altogether, our inferences for the risk of death with deferral for the first analysis (CD4+ count of 350 to 500 cells per cubic millimeter) remain similar (relative risk [RR], 1.70; P<0.001); for the second analysis (CD4+ count of more than 500 cells per cubic millimeter) the risk of death with deferral was slightly attenuated but still statistically significant (RR, 1.53; P<0.001).
In response to Hernán and Robins: we concur that we defined our "early"-therapy group according to whether patients initiated therapy when their CD4+ counts were above each of the two thresholds of interest within a defined window of time. They approach the question slightly differently, defining early therapy only in accordance with time. However, if we define early initiation only according to time, as they suggest, the results of our first analysis remain similar to what we reported (RR, 1.70; P=0.006) and the results of the second analysis are only slightly attenuated (RR, 1.76; P=0.002). We were pleased to see that the preliminary results reported with the use of their methods1 for initiation at a CD4+ count of less than 350 cells per cubic millimeter as compared with initiation at a count of less than 500 cells per cubic millimeter were nearly identical (RR, 1.68; 95% confidence interval, 1.05 to 2.69) to what we reported.
The time frame we defined for initiating antiretroviral therapy best reflects what occurs in clinical practice. We are currently preparing a separate manuscript that will outline the influence of these and other choices on our estimated effect of deferral and note that sensitivity analyses consistently show an increased risk of death with deferral of antiretroviral therapy.
Last, the letters from Gelinck and van der Ende and from Arribas et al. highlight the potential for our results to be confounded. We acknowledge this concern and note that this was the motivation for the simulations in which we found that unmeasured confounding factors would need to have a substantial association with both therapy deferral and mortality in order to have mitigated our results. We are collecting many of the variables noted by these authors and look forward to updating our analyses when these data are available.
Mari M. Kitahata, M.D., M.P.H.
University of Washington
Seattle, WA
kitahata{at}u.washington.edu
Stephen J. Gange, Ph.D.
Richard D. Moore, M.D., M.H.S.
Johns Hopkins University
Baltimore, MD
References
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