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Robert A. Larsen, M.D.
University of Southern California
Los Angeles, CA 90033
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Of the 14 patients who died and had cerebrospinal fluid opening pressures recorded, 13 had elevated pressures at their last lumbar puncture. We might expect that patients dying of cryptococcal meningitis would have increased cerebrospinal fluid pressures as their conditions deteriorated. How many patients were known to have high opening pressures at base line? Was a high base-line opening pressure predictive of mortality or clinical failure in the group as a whole?
Barry S. Zingman, M.D.
Montefiore Medical Center
Bronx, NY 10467
References
To the Editor: Dr. Larsen expresses concern about our study design and a potential bias effect on the outcome. There is no important bias from a "healthy-survivor effect" in our study. Of the 381 patients who participated in step one, 42 (11 percent) reached the study end point or were not eligible for step two. Among the other 33 patients not continuing on to step two, 21 withdrew voluntarily and 12 were excluded because of concomitant medications. Even if all 33 of these patients were deemed "unhealthy" survivors, 80 percent of our step-one patients advanced to step two, and 30 percent had positive cultures at the end of week 2.
Dr. Larsen's extrapolation of our 2-week results to reflect 10-week results and his comparison with previous studies are inappropriate. Of the 306 patients randomly assigned to consolidation therapy, 57 percent were nonresponders (composite response) at 2 weeks, but 65 percent of these showed a composite response at 10 weeks. Thus, Dr. Larsen's assumption that no patients responded to consolidation with azole therapy is incorrect. In addition, the intention-to-treat design of our study required a negative cerebrospinal fluid culture at week 10 for success; if a cerebrospinal fluid culture was not obtained from a patient the treatment was judged a mycologic failure in that patient. Of the 306 step-two patients, 83 did not have week-10 cultures, and the treatment was therefore classified as a failure in those patients. The overall composite response at week 10 was at least 45 percent, and the overall clinical response rate was 69 percent. Moreover, our two-week survival rate of 5.5 percent was strikingly low. Dr. Larsen also alludes to a study with a success rate of 100 percent among patients receiving amphotericin B plus flucytosine.1 These results were obtained in a small cohort of six patients who had normal mental status at base line (low risk for progression). In another small, nonrandomized trial, the use of flucytosine plus fluconazole did indeed achieve a 63 percent "success" rate; however, serious toxicity occurred in 62 percent of the participants, and 28 percent had to stop therapy because of severe toxicity.2 Accordingly, we believe that our conclusion is justified: Higher-dose amphotericin B plus flucytosine followed by consolidation with oral fluconazole should now be considered the treatment of choice for AIDS-associated cryptococcal meningitis.
With respect to Dr. Larsen's final point and to Dr. Zingman's letter, the patients who had positive cultures at week 2 did indeed have a higher risk of positive cultures at week 10. However, there was no difference in long-term outcome with regard to relapse or survival based on a positive culture at week 2. Moreover, in a separate study of maintenance therapy, the relapse rate over a period of 12 months among patients who received flucytosine plus amphotericin B during the first 2 weeks of therapy was significantly lower than the rate in patients who did not receive flucytosine.3 With regard to Dr. Zingman's last point, elevated base-line cerebrospinal fluid opening pressures did predict mortality; however, elevated pressure was not associated with mycologic failure or relapse.
There was an error in our published report, on page 18, in the first sentence under the heading "Deaths." It should have read, "During step one, 21 patients (5.5 percent) died: 11 of 179 in the amphotericin B group and 10 of 202 in the combination group. . . ."
Michael S. Saag, M.D.
Gretchen A. Cloud, M.S.
University of Alabama at Birmingham
Birmingham, AL 35294-2050
Charles van der Horst, M.D.
University of North Carolina
Chapel Hill, NC 27599-7030
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