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Antimicrobial Agents and Chemotherapy, January 2002, p. 248-250, Vol. 46, No. 1
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.1.248-250.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Antigen Clearance during Treatment of Disseminated Histoplasmosis with Itraconazole versus Fluconazole in Patients with AIDS

L. Joseph Wheat,^1,2,3,* Patricia Connolly,^1,3 Nicholas Haddad,^3, Ann Le Monte,^1,3 Edward Brizendine,³ and Richard Hafner^4,

Histoplasmosis Reference Laboratory,¹ Veterans’ Affairs Medical Cente, Indianapolis, Indiana,² Indiana University School of Medicine,³ Indiana Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health, Rockville, Maryland⁴

Received 25 July 2001/ Returned for modification 17 September 2001/ Accepted 10 October 2001

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Antifungal treatment reduces the concentration of Histoplasma antigen in blood and urine, supporting a hypothesis that antigen clearance could be used to compare the activity of new agents for treating histoplasmosis. In separate trials in patients with AIDS, clinical response was similar with itraconazole (85%) and fluconazole (74%). Fungal blood cultures at week 4, however, were negative in a significantly higher proportion of patients treated with itraconazole (92.3%) than in those treated with fluconazole (61.9%) (P = 0.017). Baseline antigen concentrations were similar in the two groups: serum, P = 0.7235; and urine, P = 0.1360. After 4 weeks of treatment, the decline in antigen from baseline in serum was similar in the two treatment groups (P = 0.5237), as it was in urine (P = 0.4679). At week 12, the decline in antigen from baseline in serum also was similar in the two groups (P = 0.4911) and in urine (P = 0.2786). More rapid clearance of fungemia suggests that itraconazole is more effective than fluconazole in treating histoplasmosis. This study demonstrates that clearance of fungemia is a better measure of antifungal effect than clearance of antigen.

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Disseminated histoplasmosis is a common and serious opportunistic infection among patients with AIDS, especially in areas with a high prevalence of Histoplasma capsulatum infection. Human immunodeficiency virus-infected patients with disseminated histoplasmosis require induction treatment to reverse the clinical illness and suppress the fungal burden in the tissues, followed by chronic maintenance therapy to prevent relapse (3). The standard drug has been amphotericin B, which is both inconvenient and toxic (9, 11). Oral therapy with itraconazole or fluconazole was demonstrated to be effective as induction therapy for patients with mild or moderately severe histoplasmosis in two prospective clinical trials (5, 6). Eligibility criteria, patient selection, and response criteria were designed to be similar for the itraconazole and fluconazole studies to permit assessment of relative effectiveness. In both studies, treatment outcome was assessed by resolution of clinical findings, clearance of positive blood cultures, and drug tolerance. Overall, 85% of patients responded to induction with itraconazole versus 74% for fluconazole.

A secondary objective of both studies was to determine the effect of therapy on the clearance rate of Histoplasma antigen from blood and urine. Earlier studies had demonstrated that treatment significantly reduced the antigen concentrations in the blood and urine of patients with histoplasmosis (5, 6). We decided to test the hypothesis that antigen clearance would complement measurements of clinical outcome in assessment of the antifungal activity of new agents for the treatment of histoplasmosis. For this purpose, stored samples from patients in the two treatment studies were tested in the same antigen assay to eliminate interassay variability.

Patient groups. Enrollment into the itraconazole study occurred in 1991 and 1992 (5), followed by the fluconazole study in 1992 and 1993 (6). Study entry required diagnosis of a first episode of disseminated histoplasmosis, as defined previously (5, 6). Patients were excluded if they had severe disease, as defined elsewhere. Treatment regimens and study assessments also were reviewed elsewhere (5, 6).

Histoplasma antigen assay. The test used to detect antigen in serum and urine is an enzyme-linked immunoassay that has been previously described (2). Urine and blood specimens were obtained for measurement of antigen concentrations on enrollment and at weeks 2, 4, 8, and 12 in the fluconazole study and at weeks 1, 2, 4, 8, and 12 in the itraconazole study. Initially, the baseline and week 12 specimens were compared. Analysis of those results prompted a second experiment in which baseline and week 4 specimens were tested. If baseline specimens were unavailable, week 1 specimens were acceptable as replacements. Similarly, if specimens at week 4 were not available, specimens between weeks 4 and 6 were tested, and if specimens at week 12 were not available, the date closest to week 12 between weeks 10 and 20 was used (6).

For this analysis of antigen clearance, patients who failed treatment, those with negative results at baseline, and those for whom paired baseline and completion of induction specimens were not available were excluded. For the comparison of baseline and week 4, some cases were excluded because baseline specimens were exhausted in the prior experiment comparing the baseline and week 12.

Statistical methods. Continuous outcomes are presented as mean ± 1 standard deviation and are compared using either Student’s t test or the Wilcoxon’s rank sum test. Categorical outcomes are presented as frequency occurring and percentages and are compared using Pearson’s chi-square test for independence. Bonferroni’s procedure was used to adjust P values when multiple comparisons were made. A significance level of = 0.05 was used to test all hypotheses.

The baseline characteristics that may reflect severity of infection were similar between the two studies, except for prior antiretroviral use (Table 1). A higher proportion of subjects in the itraconazole study had received antiretroviral treatment before entry than in the fluconazole study (P = 0.006). Nevertheless, CD4 counts were similar, suggesting that immune status was comparable in the two groups. Fungemia cleared more rapidly with itraconazole than with fluconazole (Table 2). At week 4, 92.3% in the itraconazole treatment group had negative fungal blood cultures, which is significantly higher than 61.9% in the fluconazole treatment group (P = 0.017). Clearance of fungemia by week 4 of therapy, however, did not predict subsequent response. Of the 38 subjects with negative cultures at week 4 in the fluconazole study, 14 (36.8%) subsequently failed or relapsed, compared to 8 of 17 (47.1%) with positive cultures (P = 0.557).

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TABLE 1. Comparison of baseline parameters in patients with AIDS and histoplasmosis treated with itraconazole versus fluconazolea

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TABLE 2. Comparison of clearance of fungemia in patients with AIDS and histoplasmosis treated with itraconazole versus fluconazolea

A comparison of baseline, week 4, and week 12 antigen levels is shown in Table 3. The data in Table 3 represent two separate experiments; the first comparing the baseline with week 12 and the second comparing the baseline with week 4. Unfortunately, many baseline specimens were depleted when the second experiment was conducted, explaining the reduced number of patients in the comparison of weeks 0 and 4. Furthermore, some of the week 12 specimens were depleted in the first experiment, preventing incorporation of specimens from weeks 0, 4, and 12 in the same assay. Only cases with paired specimens were included. As a consequence, baseline results differ, since not all patients had both week 4 and week 12 specimens and since fewer cases could be examined in the baseline-versus-week 4 analysis. After acknowledgment of these limitations of the analysis of antigen clearance, no differences in clearance were noted with itraconazole versus fluconazole. After 4 weeks of therapy, antigen levels (mean ± 1 standard deviation) in serum fell by 3.46 ± 3.84 U in the itraconazole group (n = 10) compared to 2.57 ± 3.65 U in the fluconazole group (n = 35) (P = 0.5237). Antigen levels in urine fell by 1.30 ± 2.31 U with itraconazole therapy (n = 21) versus 0.82 ± 2.80 U with fluconazole therapy (n = 41) (P = 0.4679). After 12 weeks of therapy, antigen levels in serum fell by 6.26 ± 5.14 U in the itraconazole group (n = 33) compared to 5.46 ± 4.81 U in the fluconazole group (n = 41) (P = 0.4911). Antigen levels in urine fell by 3.16 ± 2.98 U with itraconazole therapy (n = 42) versus 3.90 ± 3.22 U with fluconazole therapy (n = 44) (P = 0.2786).

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TABLE 3. Comparison of clearance of antigenemia and antigenuria in patients with AIDS and histoplasmosis treated with itraconazole versus fluconazolea

We have tested the hypothesis that measurement of antigen clearance may be a useful method of comparing the antifungal activity of new medications, having previously shown its promise in studies of experimentally induced histoplasmosis (1). In the animal studies, results of antigen clearance paralleled those of quantitative culture (1).

While nonrandomized studies have assessed the effectiveness of itraconazole (5) and fluconazole (6) for treatment of histoplasmosis, comparative trials have not been possible because of the large sample size required for such a study. However, those studies were developed using similar eligibility criteria with the goal of permitting an assessment of the relative effectiveness of the two agents. As noted in Table 1, the baseline characteristics of the patients in the two studies were comparable, except for prior antiretroviral use. CD4 counts, however, and fungal blood culture positivity were similar in the two studies, suggesting that immune status and severity of histoplasmosis were comparable. Thus, a comparison of the effect of itraconazole and fluconazole therapy on antigen clearance and clearance of fungemia seemed justified.

Clinical response rates to induction therapy were similar in the two studies, 85% with itraconazole and 74% with fluconazole. Although the median time to resolution of fever was 1 week in both studies, weight gain occurred more rapidly with itraconazole (median, 1 week) than fluconazole (median, 4 weeks). Fungemia at week 4 cleared more rapidly with itraconazole than fluconazole (P = 0.017). Of note is that culture positivity at week 4 did not distinguish patients who subsequently failed or relapsed from those to responded to therapy.

Similar antigen clearance rates with the two treatments disagree with the more rapid clearance of fungemia with itraconazole than with fluconazole. Of note, however, is that the comparison of clearance of antigen was hampered by the reduction in number of evaluable cases due to depletion of specimens, particularly sera. In the animal studies, antigen clearance paralleled culture clearance and both occurred more completely with itraconazole than with fluconazole (4). The animal studies, however, were tightly controlled, compared to these clinical trials, in that all animals received the same inoculum and that specimens were obtained at specific times following infection in all animals.

We recently contrasted clearance of fungemia and antigen in patients treated with itraconazole, described here, versus liposomal amphotericin B (7). Although a combined comparison of liposomal amphotericin B, itraconazole, and fluconazole would have been of interest, liposomal amphotericin B was only given for the first 2 weeks and week 2 blood culture results were not obtained in the fluconazole study. Thus, comparison of clearance of fungal burden during fluconazole versus liposomal amphotericin B would not have been possible. The present study supplements the earlier report and permits us to contrast the clearance of fungemia in these two studies. Accordingly, the following hierachy of antifungal activity for H. capsulatum emerges: liposomal amphotericin B clears fungemia most rapidly, followed by itraconazole and then fluconazole. Whether clinical response rate would follow that pattern requires a prospective randomized trial, however.

In conclusion, the more rapid clearance of fungemia with itraconazole than fluconazole differs from the similar rate of antigen clearance and suggests that measurement of fungemia provides a better marker for response to therapy than does antigen. Limitations of this study include the fact that the study data were not obtained from a randomized comparison of both therapies and that antigen data were unavailable for several patients. Because of these limitations, we refrain from trying to establish equivalence of the clearance rates even though we failed to show a significant difference between the rates. Prior studies have established the role of antigen detection for the initial diagnosis of histoplasmosis (10) and for evaluation of relapse (8). Antigen levels must be measured at the end of induction therapy, every 3 to 6 months during maintenance therapy, and at the time of suspected relapse to assist in the diagnosis of relapse.

 
The two studies were sponsored by the AIDS Clinical Trials Group (AI 25859) and the Mycoses Study Group of the National Institute of Allergy and Infectious Diseases (NIAID contract no. NO1-AI65296). Pfizer Central Research was the pharmaceutical sponsor for the fluconazole trial and Janssen Research Foundation for the itraconazole trial.

 
* Corresponding author. Mailing address: Indiana University School of Medicine, Histoplasmosis Reference Laboratory, 1001 West Tenth St., OPW 430, Indianapolis, IN 46202-2879. Phone: (317) 630-6262. Fax: (317) 630-7522. E-mail: lwheat{at}iupui.edu.

Member of the AIDS Clinical Trials Group and the Mycoses Study Group of the National Institute of Allergy and Infectious Diseases.

Present address: Washington University School of Medicine, St. Louis, Mo.

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1. Connolly, P., J. Wheat, C. Schnizlein-Bick, M. Durkin, S. Kohler, M. Smedema, J. Goldberg, E. Brizendine, and D. Loebenberg. 1999. Comparison of a new triazole antifungal agent, Schering 56592, with itraconazole and amphotericin B for treatment of histoplasmosis in immunocompetent mice. Antimicrob. Agents Chemother. 43:322–328.[Abstract/Free Full Text]
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2. Durkin, M. M., P. A. Connolly, and L. J. Wheat. 1997. Comparison of radioimmunoassay and enzyme-linked immunoassay methods for detection of Histoplasma capsulatum var. capsulatum antigen. J. Clin. Microbiol. 35:2252–2255.[Abstract]
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3. Hecht, F. M., J. Wheat, A. H. Korzun, R. Hafner, K. J. Skahan, R. Larsen, M. T. Limjoco, M. Simpson, D. Schneider, M. C. Keefer, R. Clark, K. K. Lai, J. M. Jacobson, K. Squires, J. A. Bartlett, and W. Powderly. 1997. Itraconazole maintenance treatment for histoplasmosis in AIDS: a prospective, multicenter trial. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 16:100–107.[Medline]
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4. LeMonte, A., K. Washum, M. Smedema, C. Schnizlein-Bick, R. Kohler, and L. J. Wheat. 2000. Amphotericin B combined with itraconazole or fluconazole for treatment of histoplasmosis. J. Infect. Dis. 182:545–550.[CrossRef][Medline]
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5. Wheat, J., R. Hafner, A. H. Korzun, M. T. Limjoco, P. Spencer, R. A. Larsen, F. M. Hecht, W. Powderly, and AIDS Clinical Trial Group. 1995. Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. Am. J. Med. 98:336–342.[CrossRef][Medline]
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6. Wheat, J., S. MaWhinney, R. Hafner, D. McKinsey, D. F. Chen, A. Korzun, K. J. Skahan, P. Johnson, R. Hamill, D. Bamberger, P. Pappas, J. Stansell, S. Koletar, K. Squires, R. A. Larsen, T. Cheung, N. Hyslop, K. K. Lai, D. Schneider, C. Kauffman, M. Saag, W. Dismukes, and W. Powderly. 1997. Treatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. Am. J. Med. 103:223–232.[CrossRef][Medline]
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7. Wheat, L. J., G. Cloud, P. C. Johnson, P. Connolly, M. Goldman, A. Le Monte, D. E. Fuller, T. E. Davis, R. Hafner, the AIDS Clinical Trials Group, and the Mycoses Study Group of NIAID. 2001. Clearance of fungal burden during treatment of disseminated histoplasmosis with liposomal amphotericin B versus itraconazole. Antimicrob. Agents Chemother. 45:2354–2357.[Abstract/Free Full Text]
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8. Wheat, L. J., P. Connolly-Stringfield, R. Blair, K. Connolly, T. Garringer, and B. P. Katz. 1991. Histoplasmosis relapse in patients with AIDS: detection using Histoplasma capsulatum variety capsulatum antigen levels. Ann. Intern. Med. 115:936–941.
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9. Wheat, L. J., P. A. Connolly-Stringfield, R. L. Baker, M. F. Curfman, M. E. Eads, K. S. Israel, S. A. Norris, D. H. Webb, and M. L. Zeckel. 1990. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore) 69:361–374.[Medline]
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10. Wheat, L. J., R. B. Kohler, and R. P. Tewari. 1986. Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens. N. Engl. J. Med. 314:83–88.[Abstract]
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11. Wheat, L. 1996. Histoplasmosis in the acquired immunodeficiency syndrome. Curr. Top. Med. Mycol. 7:7–18.[Medline]

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Antimicrobial Agents and Chemotherapy, January 2002, p. 248-250, Vol. 46, No. 1
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.1.248-250.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wheat, L. J. Articles by Hafner, R. Search for Related Content PubMed PubMed Citation Articles by Wheat, L. J. Articles by Hafner, R.