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CD4 Counts as Surrogate Markers for Progression to AIDS
- Sungsub Choi, PhD;
- Stephen Lagakos, PhD; and
- Robert Schooley, MD
- McGill University; Montreal, Quebec; Canada H3A 1A2 Harvard University; Boston, MA 02115 University of Colorado; Denver, CO 80262
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IN RESPONSE:
Dr. Nightingale suggests the logarithm of the CD4 count is a good predictor of 1-year survival. Similarly, we found that CD4 count—either baseline or current value—was highly prognostic for progression to AIDS. This issue, however, does not address the value of the CD4 count as a surrogate marker for disease progression. In the latter, the question is essentially whether a patient whose CD4 count is elevated by therapeutic intervention will have a corresponding reduction in risk equalling that of an untreated patient with a similar post-treatment CD4 count. Our data indicated that the actual reduction in risk exceeded that explainable by the increased CD4 count; that is, a person whose CD4 count was elevated by zidovudine had a lower risk than did a placebo recipient with the same post-treatment CD4 count.
Regarding our use of the Cox proportional-hazards model, it does not assume a constant risk but rather allows the risk to be arbitrary over time. In its simplest form, the Cox model assumes that the relative risk of two treatment groups is constant over time; that is, the risks for progression in the two groups are proportional over time. As we noted in our study, we found that this assumption appeared to have been violated.
We sympathize with Dr. Nightingale's concern about the definition of a surrogate marker. Our definition assumes that all of the treatment's benefit was explainable through its effect on the CD4 count. If true, the clinical impact of a new therapy could be safely assessed solely by its effect on the CD4 count. If untrue, however, a treatment's effect (or lack of effect) on the CD4 count might not reflect its effect on clinical progression, and assessment of a drug based only on CD4 count could therefore be misleading. On these grounds, the definition of an “ideal” surrogate marker is appropriate. In practice, however, it is unrealistic to expect that any laboratory or clinical marker could explain all of a treatment's effect. This factor must be considered when drawing conclusions about the usefulness of a marker that only partially explains a treatment's clinical benefit.
Dr. Hirschel seems to have misunderstood our results. We found that, in asymptomatic patients, both CD4 counts and the rate of progression to AIDS were improved by zidovudine. We also found, however, that the latter benefit could not be fully explained by the former.
Dr. Phillips and Ms. Sabin make several important points. They are correct that the range of 0% to 37% is not a confidence interval. Indeed, the measurement error associated with the observed CD4 values could lead one to conclude that CD4 explains less of zidovudine's effect than it does.
Dr. Harris appears to have missed the point of the article. The purpose was not to assess whether “zidovudine does work” nor to determine whether zidovudine affects CD4 cells.
- Copyright ©2004 by the American College of Physicians
