Skip Navigation

Safety of Discontinuation of Maintenance Therapy for Disseminated Histoplasmosis after Immunologic Response to Antiretroviral Therapy

  1. Mitchell Goldman1,
  2. Robert Zackin2,
  3. Carl J. Fichtenbaum3,
  4. Daniel J. Skiest4,
  5. Susan L. Koletar5,
  6. Richard Hafner6,
  7. L. Joseph Wheat1,a,
  8. Peter M. Nyangweso2,
  9. Constantin T. Yiannoutsos2,a,
  10. Carol T. Schnizlein-Bick1,
  11. Susan Owens7,
  12. Judith A. Aberg8,a, and
  13. AIDS Clinical Trials Group A5038 Study Groupb
  1. 1Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis, Indiana
  2. 2Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts
  3. 3University of Cincinnati College of Medicine, Cincinnati, Ohio
  4. 4Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas
  5. 5Division of Infectious Diseases, Ohio State University, Columbus
  6. 6Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
  7. 7Frontier Science and Technology Research Foundation, Amherst, New York
  8. 8Washington University School of Medicine, St. Louis, Missouri
  1. Reprints or correspondence: Dr. Mitchell Goldman, Indiana University School of Medicine, Div. of Infectious Diseases, Wishard Memorial Hospital (Rm. OPW-430), 1001 W. 10th St., Indianapolis, IN 46202 (mgoldman{at}iupui.edu).

  • ↵a Present affiliations: MiraVista Diagnostics and MiraBella Technologies, Indianapolis, IN (L.J.W.); Division of Biostatistics, Indiana University School of Medicine, Indianapolis (C.T.Y.); and New York University Medical Center, New York (J.A.A.).

 
Next Section

Abstract

We performed a prospective observational study to assess the safety of stopping maintenance therapy for disseminated histoplasmosis among human immunodeficiency virus–infected patients after response to antiretroviral therapy. All subjects received at least 12 months of antifungal therapy and 6 months of antiretroviral therapy before entry. Negative results of fungal blood cultures, urine and serum Histoplasma antigen level of <4.1 units, and CD4+ T cell count of >150 cells/mm3 were required for eligibility. Thirty-two subjects were enrolled; the median CD4+ T cell count at study entry was 289 cells/mm3. No relapses of histoplasmosis occurred after a median duration of follow-up of 24 months. This corresponded to an observed relapse rate of 0 cases per 65 person-years. The median CD4+ T cell count at final study visit was 338 cells/mm3. Discontinuation of antifungal maintenance therapy appears to be safe for patients with acquired immunodeficiency syndrome with previously treated disseminated histoplasmosis and sustained immunologic improvement in response to antiretroviral therapy.

Disseminated histoplasmosis is a serious opportunistic infection, occurring in 3%–5% of patients with AIDS living within the areas of endemicity in North America. This infections usually develops after CD4+ T cell counts decrease to <150 cells/mm3 [1, 2]. Antifungal therapy is highly effective for initial therapy, but relapse was extremely common before the use of continuous maintenance therapy and before the availability of effective antiretroviral therapies for HIV infection [2]. Because maintenance therapy for histoplasmosis after a response to induction antifungal therapy was demonstrated to reduce the relapse rate to ∼5%, lifelong maintenance therapy with itraconazole has been the standard of care for this infection [3].

The use of potent combination antiretroviral therapy has been associated with dramatic reductions in the incidence of opportunistic infections [4, 5]. Studies have demonstrated that primary and secondary prophylaxis (or maintenance therapies) for Pneumocystis carinii pneumonia [6, 7], disseminated Mycobacterium avium complex infection [8–11], cryptococcal meningitis [12–15], and cytomegalovirus retinitis [16, 17] can be safely discontinued after a sustained increase in the CD4+ T cell count to greater than the values associated with the risk of developing the specific opportunistic infection.

On the basis of these observations demonstrating the safety of discontinuing maintenance therapy for other opportunistic infections, we designed a study to assess the safety of discontinuing antifungal maintenance therapy for patients with successfully treated AIDS-related histoplasmosis and response to antiretroviral therapy.

Previous SectionNext Section

Patients and Methods

Study participants. Study subjects had documented HIV infection, previous disseminated histoplasmosis, and documented remission from disseminated histoplasmosis after receiving at least 12 months of antifungal maintenance therapy with systemic antifungals (e.g., itraconazole fluconazole, or amphotericin B). Evidence of previous histoplasmosis was defined as recovery of Histoplasma capsulatum from culture; identification of organisms consistent with H. capsulatum in stains; or detection of high levels of Histoplasma antigen (⩾4.1 units) in urine samples, serum samples, or bronchoalveolar lavage fluid). Remission from disseminated histoplasmosis was defined as the absence of signs, symptoms, or laboratory abnormalities consistent with active disease, Histoplasma antigen concentrations of <4.1 units in urine and serum specimens, and a negative result of a fungal blood culture. Subjects were required to have 2 CD4+ T cell counts of >150 cells/mm3 obtained within 6 months (performed ⩾1 week apart), with one sample obtained within 30 days of entry. Subjects were required to have received antiretroviral therapy for ⩾24 consecutive weeks and to be treated with the same regimen for ⩾8 consecutive weeks before study entry.

The protocol was open to persons aged ⩾13 years who were willing and able to provide informed consent. Subjects aged <18 years required written informed consent of a parent or guardian. Women of childbearing potential were required to have a negative pregnancy test result. Receipt of immunosuppressive medications within 2 months, presence of any acute systemic infection, requirement for continued treatment with systemic antifungal agents, or meningitis or lesions of the brain or spinal cord attributed to histoplasmosis were all exclusionary criteria.

Study end point determinations (relapse of histoplasmosis). Proven relapse of histoplasmosis was defined as a culture positive for H. capsulatum or a fungal stain of tissue or body fluid specimens consistent with H. capsulatum. Probable relapse of histoplasmosis was defined as the presence of clinical findings suggestive of relapsed histoplasmosis along with a single increase in Histoplasma antigen of ⩾4.1 units or the demonstration of increases in antigen levels on consecutive testing of ⩾4.1 units in the absence of clinical findings.

Routine study procedures. At study entry, subjects discontinued maintenance therapy for disseminated histoplasmosis. Subjects underwent clinical evaluations at 4 weeks, 8 weeks, and every 8 weeks after enrollment. Hematological examination and liver function tests (i.e., determination of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, and lactate dehydrogenase levels), fungal blood cultures, and serum and urine Histoplasma antigen tests were performed at each study visit. Samples for fungal blood cultures (BACTEC Myco/F Lytic) and samples for Histoplasma antigen quantitation (Histoplasmosis Reference Laboratory; Indianapolis, IN) were obtained and shipped to centralized reference laboratories at Indiana University Medical Center (Indianapolis).

CD4+ T cell determinations were performed at baseline and every 8 weeks thereafter. Plasma samples were obtained for determination of HIV-1 RNA level at baseline and every 8 weeks thereafter, with testing performed at a centralized laboratory (Johns Hopkins Virology Laboratory; Baltimore, MD) using the UltraSensitive Roche Amplicor HIV-1 Monitor (level of detection, <50 copies/mL) after study completion.

Evaluations for subjects with suspected relapse of histoplasmosis. Subjects with suspected recurrence of histoplasmosis included subjects who developed clinical or routine laboratory findings consistent with histoplasmosis, as well as subjects discovered to have serum or urine Histoplasma antigen increases of ⩾2 units, compared with the last stable value. Clinical signs and symptoms or routine laboratory results included the following: ⩾2 days of temperature >38°C; night sweats or diarrhea; weight loss of >5% body weight; hepatomegaly; splenomegaly; unexplained lesions of skin, mouth, colon, or brain lesions detected on brain scan; alkaline phosphatase level of ⩾2 times the upper limit of normal; development of unexplained anemia (hemoglobin level, <7 g/dL) or thrombocytopenia (thrombocyte level, <50,000/mm3); pulmonary complaints with infiltrates on a chest radiograph; meningitis or focal neurologic complaints; or a sepsis syndrome with hypotension, respiratory failure, coagulopathy, and multiorgan failure. At the time of suspected relapse, physical examination, hematological examination, and liver function tests were performed, blood samples were obtained for fungal culture, and urine and serum samples were obtained for Histoplasma antigen quantitation. These studies were repeated every 2–4 weeks up to 3 times, until the findings suggestive of relapsed histoplasmosis resolved or were attributed to another illness or until the diagnosis of relapsed histoplasmosis was confirmed.

Procedures for subjects with a decrease in CD4 count to <100 cells/mm3. If a subject experienced a decrease in the CD4+ T cell count to <100 cells/mm3, an additional CD4+ T cell count was requested within 14 days. If the additional CD4+ T cell count was <100 cells/mm3, the protocol recommended reinstitution of systemic antifungal therapy.

Statistical considerations and study design. At study design, a sample size of 50 subjects was established to provide 80% power to reject a rate of proven or probable relapse of histoplasmosis in subjects discontinuing antifungal maintenance therapy of ⩾20% at the 5% level, assuming a “true” relapse rate of 7.5%. The initial study design included a 12-month accrual period and 12 months of follow-up after the last subject was enrolled.

An exact upper 95% binomial CI was constructed for the relapse proportion and an upper 95% Poisson CI was constructed for the incidence rate of histoplasmosis. For all other analyses, 2-sided α = .05 level tests were used. Statistical significance for continuous outcomes was determined with Wilcoxon tests. No adjustment for multiple comparisons was made.

Previous SectionNext Section

Results

Study subjects. Thirty-two subjects were enrolled in the study from August 1999 through September 2001 at 11 sites in the United States. The study population included 31 men and 1 woman with a median age of 40 years (range, 22–68 years). Fifty-nine percent of subjects were white, 25% were black, and 16% were Hispanic. The median baseline CD4+ T cell count was 289 cells/mm3 (range, 124–601 cells/mm3). One subject with a CD4+ T cell count of 124 cells/mm3 at baseline had met the eligibility requirements at the time of screening. Fifty-nine percent of the subjects entered the study with HIV loads of <50 copies/mL. All subjects were receiving itraconazole maintenance therapy before enrollment. One subject also reported amphotericin B use, and one other subject received fluconazole early in maintenance treatment. The median duration of antifungal maintenance therapy before study enrollment was 34 months (range, 14–81 months). All 32 subjects were receiving antifungal maintenance therapy without any interruption for >4 weeks in the 12 months before enrollment. At baseline, the median Histoplasma antigen levels were 0.7 units (range, 0.5–2.3 units) for urine and 0.6 units (range, 0.4–0.8 units) for serum.

Study follow-up. After 26 months, an interim review indicated that additional accrual beyond 32 subjects was not necessary to answer the primary study objective. At the time of study completion, 29 subjects were in active follow-up. The median length of follow-up was 24 months (range, 7–35 months), with a total of 65.3 subject-years of follow-up. With the exception of 1 subject who died at week 29 of Staphylococcus aureus sepsis, all remaining subjects were in active follow-up for ⩾12 months. Of the other 2 subjects prematurely discontinuing study participation, one was unable to travel to the clinic after week 64, and the other was unable to be contacted after week 94. The subject who died had resumed itraconazole therapy before his death because of the initiation of corticosteroids for a “sarcoidosis-like” illness. This subject's CD4+ T cell count at study entry was 448 cells/mm3, and the last count before death was 529 cells/mm3. This subject had multiple Histoplasma antigen determinations, fungal cultures, histopathologic studies of lung and other tissue samples, and an eventual autopsy, none of which revealed evidence of relapsed histoplasmosis.

Changes in CD4 count and HIV-1 RNA level. Over the course of the study, the CD4+ T cell counts of subjects increased from a baseline median of 289 cells/mm3 to 338 cells/mm3 at the final determination. No subject had 2 consecutive CD4+ T cell counts of <100 cells/mm3 requiring protocol-mandated reinitiation of antifungal therapy. At baseline, 59% of subjects had HIV-1 RNA levels of <50 copies/mL (range, <50–45,244 copies/mL), and at the last study visit, the HIV-1 RNA level was <50 copies/mL in 81% of subjects.

Study end points. No subject developed either proven or probable histoplasmosis. The observed incidence of relapse was 0 cases per 65.3 person-years of observation (upper 95% CI, 4.6 cases per 100 person-years). The proportion of subjects experiencing relapse was 0 (0%) of 32 (upper 95% CI, 8.94). H. capsulatum was not recovered from any blood culture. Three subjects required additional evaluations for suspected relapse of histoplasmosis. These evaluations were initiated as a result of isolated elevations of Histoplasma antigen levels in urine to >2.0 but <4.1 units for 1 subject and clinical or other laboratory findings for 2 subjects. No subject demonstrated an elevation in serum or urine antigen value of >4.1 units at any time during study follow-up.

Previous SectionNext Section

Discussion

This study was designed to demonstrate whether discontinuation of maintenance antifungal therapy is safe for AIDS patients with a history of ⩾12 months of treatment for disseminated histoplasmosis and immunologic improvement after treatment with antiretroviral therapy. The median study follow-up duration was 24 months, with minimal loss to follow-up. The relapse rate observed during this study was less than the hypothesized rate of 7.5% with 95% confidence. This low relapse rate is in marked contrast to the 60%–80% relapse rates in studies conducted before use of continuous antifungal maintenance therapy and the availability of potent antiretroviral therapy [2]. It is unlikely that cases of relapsed histoplasmosis were overlooked because of the frequency of follow-up visits and use of a Histoplasma antigen test, a test with a high sensitivity for relapsed histoplasmosis in patients with AIDS [18, 19].

Our study required subjects to have completed previous induction treatment and a minimum of 12 months of maintenance antifungal therapy. A recent abstract from Argentina reported 39 HIV-infected patients with a response to antiretroviral therapy (CD4+ T cell count >150 cells/mm3) who discontinued antifungal therapy for histoplasmosis after receiving ⩾6 months of antifungal maintenance therapy [20]. No relapse was reported after a median duration of follow-up of 16 months. Although discontinuation of antifungal maintenance therapy at a CD4+ T cell count >150 cells/mm3 appears to be safe, the precise level of CD4+ T cells that results in restoration of immunity to histoplasmosis is unknown; it may in fact be lower. The CD4+ T cell count value for reinitiation of antifungal maintenance therapy has also not been defined, but a decrease to <100 cells/mm3 is a reasonable criterion for reinstitution.

In conclusion, this study indicates that it appears safe to discontinue maintenance antifungal therapy for patients with AIDS who have received ⩾12 months of antifungal therapy for disseminated histoplasmosis and who experienced sustained immunologic improvement as a result of antiretroviral therapy.

Previous SectionNext Section

Study Group Members

Additional members of the AIDS Clinical Trials Group A5038 Study Team include Janet W. Anderson (statistical support), Lynette Purdue (protocol pharmacist), Richard McVey (protocol field representative), William Wade (protocol Community Constituency Group representative), Nancy Webb (protocol laboratory data coordinator), Linda Lambrecht (protocol laboratory technologist), and Susan A. Kelly and Evelyn Hogg (clinical trials specialist).

AIDS Clinical Trials Group A5038 Study Sites and Contributors: University of Texas Southwestern: Daniel J. Skiest, Tianna Petersen, grant AI 467376; University of Cincinnati: Carl J. Fichtenbaum, Patricia Kohler, grant AI 25897; Indiana University Hospital: Mitchell Goldman, Jean A. Craft, Scott Hamilton, grant AI 25859; Ohio State: Susan L. Koletar, Jane Russell, grant AI 25924; University of Southern California: Susan Cahill, Gary Dyak, grant AI 27670; Emory University: Jeffrey L. Lennox, Karen Chan; NYU Bellevue: Olivia Ortiz, Maura Laverty, grant AI 027665; University of Nebraska Medical Center: Susan Swindells, Frances Van Meter; Washington University: Judith Aberg, Michael Conklin, grant AI 25903; Cook County Core Center Joseph Pulvirenti, Joanne Despotes.

Previous SectionNext Section

Footnotes

  • Conflict of interest: L.J.W. presently owns and manages MiraVista Diagnostics and MiraBella Technologies (Indianapolis, IN), a company that presently performs the Histoplasma antigen clinical test used in this study.

  • Financial support: Adult AIDS Clinical Trials Group, which is funded by the National Institute of Allergy and Infectious Diseases (grants AI 25859, AI 25897, AI 38855, AI 467376, AI 25924, and AI 25903).

  • ↵b Members of the study group are listed at the end of the text.

  • Received December 15, 2003.
  • Accepted January 22, 2004.
Previous Section
 

References

  1. ↵
    1. Wheat J
    . Histoplasmosis in the acquired immunodeficiency syndrome. Curr Top Med Mycol 1996;7:7-18.
    Medline
  2. ↵
    1. Wheat LJ,
    2. Connolly-Stringfield PA,
    3. Baker RL,
    4. et al
    . Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine 1990;69:361-74.
    Medline
  3. ↵
    1. Wheat J,
    2. Hafner R,
    3. Wulfsohn M,
    4. et al
    . Prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome. The National Institute of Allergy and Infectious Diseases Clinical Trials and Mycoses Study Group Collaborators. Ann Intern Med 1993;118:610-6.
    Abstract/FREE Full Text
  4. ↵
    1. Palella FJ Jr,
    2. Delaney KM,
    3. Moorman AC,
    4. et al
    . Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators [comment]. N Engl J Med 1998;338:853-60.
    CrossRefMedlineWeb of Science
  5. ↵
    1. Ledergerber B,
    2. Egger M,
    3. Erard V,
    4. et al
    . AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study [comment]. JAMA 1999;282:2220-6.
    Abstract/FREE Full Text
  6. ↵
    1. Lopez Bernaldo de Quiros JC,
    2. Miro JM,
    3. Pena JM,
    4. et al
    . A randomized trial of the discontinuation of primary and secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with HIV infection. Grupo de Estudio del SIDA 04/98 [comment]. N Engl J Med 2001;344:159-67.
    CrossRefMedlineWeb of Science
  7. ↵
    1. Koletar SL,
    2. Heald AE,
    3. Finkelstein D,
    4. et al
    . A prospective study of discontinuing primary and secondary Pneumocystis carinii pneumonia prophylaxis after CD4 cell count increase to >200 × 106/L. AIDS 2001;15:1509-15.
    CrossRefMedlineWeb of Science
  8. ↵
    1. Currier JS,
    2. Williams PL,
    3. Koletar SL,
    4. et al
    . Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count: a randomized, double-blind, placebo-controlled trial. AIDS Clinical Trials Group 362 Study Team. Ann Intern Med 2000;133:493-503.
    Abstract/FREE Full Text
    1. El-Sadr WM,
    2. Burman WJ,
    3. Grant LB,
    4. et al
    . Discontinuation of prophylaxis for Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. Terry Beirn Community Programs for Clinical Research on AIDS. N Engl J Med 2000;342:1085-92.
    CrossRefMedlineWeb of Science
    1. Shafran SD,
    2. Mashinter LD,
    3. Phillips P,
    4. et al
    . Successful discontinuation of therapy for disseminated Mycobacterium avium complex infection after effective antiretroviral therapy [summary for patients in Ann Intern Med. 2002-137-148]. Ann Intern Med 2002;137:734-7.
    Abstract/FREE Full Text
  11. ↵
    1. Aberg JA,
    2. Williams PL,
    3. Liu T,
    4. et al
    . A study of discontinuing maintenance therapy in human immunodeficiency virus—infected subjects with disseminated Mycobacterium avium complex: AIDS Clinical Trial Group 393 Study Team. J Infect Dis 2003;187:1046-5. [Erratum appears in J Infect Dis. 2003-187-1346.].
    Abstract/FREE Full Text
  12. ↵
    1. Aberg JA,
    2. Price RW,
    3. Heeren DM,
    4. Bredt B
    . A pilot study of the discontinuation of antifungal therapy for disseminated cryptococcal disease in patients with acquired immunodeficiency syndrome, following immunologic response to antiretroviral therapy. J Infect Dis 2002;185:1179-82.
    Abstract/FREE Full Text
    1. Vibhagool A,
    2. Sungkanuparph S,
    3. Mootsikapun P,
    4. et al
    . Discontinuation of secondary prophylaxis for cryptococcal meningitis in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy: a prospective, multicenter, randomized study. Clin Infect Dis 2003;36:1329-31.
    Abstract/FREE Full Text
    1. Martinez E,
    2. Garcia-Viejo MA,
    3. Marcos MA,
    4. et al
    . Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy. AIDS 2000;14:2615-7.
    CrossRefMedlineWeb of Science
  15. ↵
    1. Rollot F,
    2. Bossi P,
    3. Tubiana R,
    4. et al
    . Discontinuation of secondary prophylaxis against cryptococcosis in patients with AIDS receiving highly active antiretroviral therapy. AIDS 2001;15:1448-9.
    CrossRefMedlineWeb of Science
  16. ↵
    1. Jouan M,
    2. Saves M,
    3. Tubiana R,
    4. et al
    . Discontinuation of maintenance therapy for cytomegalovirus retinitis in HIV-infected patients receiving highly active antiretroviral therapy. AIDS 2001;15:23-31.
    CrossRefMedlineWeb of Science
  17. ↵
    1. Macdonald JC,
    2. Torriani FJ,
    3. Morse LS,
    4. Karavellas MP,
    5. Reed JB,
    6. Freeman WR
    . Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy [comment]. J Infect Dis 1998;177:1182-7.
    Abstract/FREE Full Text
  18. ↵
    1. Wheat LJ,
    2. Kohler RB,
    3. Tewari RP
    . Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens. N Engl J Med 1986;314:83-8.
    MedlineWeb of Science
  19. ↵
    1. Wheat LJ,
    2. Connolly-Stringfield P,
    3. Blair R,
    4. Connolly K,
    5. Garringer T,
    6. Katz BP
    . Histoplasmosis relapse in patients with AIDS: detection using Histoplasma capsulatum variety capsulatum antigen levels. Ann Intern Med 1991;115:936-41.
    Abstract/FREE Full Text
  20. ↵
    1. Sued O,
    2. Abusamra O,
    3. Helou S,
    4. et al
    . Program and abstracts of the 14th International AIDS Conference. Barcelona, Spain: International AIDS Society; 2002. Discontinuation of maintenance therapy for disseminated histoplasmosis: a study of 39 patients [abstract ThPeC7476].
| Table of Contents

This Article

  1. Clin Infect Dis. (2004) 38 (10): 1485-1489. doi: 10.1086/420749
  1. AbstractFree
  2. » Full Text (HTML)Free
  3. Full Text (PDF)Free

Classifications

Share

  1. Email this article

Navigate This Article

Current Issue

  1. March 1, 2012 54 (5)
  1. Clinical Infectious Diseases
  1. Alert me to new issues

Most