Histoplasmosis in Patients With Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS)

Although discontinuation of suppressive antifungal therapy for acquired immunodeficiency syndrome (AIDS)-associated histoplasmosis is accepted for patients with immunologic recovery, there have been no published studies of this approach in clinical practice, and minimal characterization of individuals who relapse with this disease. We performed a multicenter retrospective cohort study to determine the outcome in AIDS patients following discontinuation of suppressive antifungal therapy for histoplasmosis. Ninety-seven patients were divided into a physician-discontinued suppressive therapy group (PD) (38 patients) and a physician-continued suppressive therapy group (PC) (59 patients). The 2 groups were not statistically different at baseline, but at discontinuation of therapy and at the most recent follow-up there were significant differences in adherence to therapy, human immunodeficiency virus (HIV) RNA, and urinary Histoplasma antigen concentration. There was no relapse or death attributed to histoplasmosis in the PD group compared with 36% relapse (p G 0.0001) and 5% death (p = 0.28) in the PC group. Relapse occurred in 53% of the nonadherent patients but not in the adherent patients (p G 0.0001). Sixty-seven percent of patients with initial central nervous system (CNS) histoplasmosis relapsed compared to 15% of patients without CNS involvement (p = 0.0004), which may be accounted for by nonadherence. In addition, patients with antigenuria above 2.0 ng/mL at 1-year follow-up were 12.82 times (95% confidence interval, 2.91Y55.56) more likely to relapse compared to those with antigenuria below 2.0 ng/mL. Discontinuation of antifungal therapy was safe in adherent patients who completed at least 1 year of antifungal treatment, and had CD4 counts 9150 cells/mL, HIV RNA G400 c/mL, Histoplasma antigenuria G2 ng/mL (equivalent to G4.0 units in second-generation method), and no CNS histoplasmosis. (Medicine 2014;93: 11Y18) Abbreviations: AIDS = acquired immunodeficiency syndrome, CI = confidence interval, CNS = central nervous system, CSF = cerebrospinal fluid, HAART = highly active antiretroviral therapy, HIV = human immunodeficiency virus, IDSA = Infectious Diseases Society of America, OR= odds ratio, PC= physician-continued suppressive therapy group, PD = physician-discontinued suppressive therapy group. INTRODUCTION H istoplasma capsulatum is a dimorphic fungus that is endemic in the Ohio and Mississippi River valleys of the United States and in Central and South America, and has microfoci in the eastern United States, southern Europe, Africa, and southeastern Asia. Histoplasmosis is associated with significant morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). However, limited experience has shown that antifungal therapy can be discontinued in selected patients with AIDS-associated histoplasmosis. In a study published in 2004, antifungal therapy was stopped in patients who had received at least 1 year of antifungal therapy; received 6 months of antiretroviral therapy; and had Histoplasma antigenemia and antigenuria G4.0 units, negative fungal blood cultures, and CD4 counts of at least 150 cells/KL. Of the 32 patients enrolled in the study, none relapsed. In 2007 the Infectious Diseases Society of America (IDSA) endorsed the approach outlined in the 2004 study and changed its recommendation from lifelong-maintenance antifungal therapy in the 2000 guideline to discontinuation of antifungal therapy if that study’s criteria were met. However, there is limited published evidence for this approach in clinical practice. Additionally, the study that informed the guideline did not include individuals who relapsed, and there is a paucity of published data on this subset of patients. Our objective in the current study was to evaluate outcome data from clinical practice during the highly active antiretroviral therapy (HAART) era and suggest additional considerations for discontinuation of antifungal therapy. PATIENTS AND METHODS Patients Patients were identified by review of clinical and laboratory records and International Classification of Diseases-9th revision (ICD-9) codes from October 1995 to December 2009 at the Medicine & Volume 93, Number 1, January 2014 www.md-journal.com 11 From Division of Infectious Diseases (TM, RNG), Department of Internal Medicine, and Department of Public Health (TNC), University of Kentucky, Lexington, Kentucky; Division of Infectious Diseases (AMA), Department of Internal Medicine, Emory University, Atlanta, Georgia; Division of Infectious Diseases (AS), Department of Internal Medicine, University of Southern California, Los Angeles, California; Division of Infectious Diseases (AF), Department of Internal Medicine, University Medical Center of Southern Nevada, Las Vegas, Nevada; Department of Pulmonary and Critical Care Medicine, Thoracic Transplantation (CH), Indiana University Health, Indianapolis, Indiana; Division of Infectious Disease (JWB), Department of Internal Medicine, University of Alabama, Birmingham, Alabama; Department of Epidemiology (MJ), College of Public Health, University of Louisville, Louisville, Kentucky; Division of Infectious Disease (DMB), Department of Internal Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri; and MiraVista Diagnostics (MR, LJW), Indianapolis, Indiana. Conflicts of interest: The following authors have had relationships with the companies listed: AMA: Gilead Sciences; JWB: Merck, Pfizer, Mayne Pharma, Astellas; RNG: Pfizer, Bavarian Nordic, Pazvax, Virapharma, GlaxoSmithKline; DMB: Gilead, Viral Ed; MR: MiraVista Diagnostics; LJW: MiraVista Diagnostics and MiraBella Technologies. Reprints: Thein Myint, Division of Infectious Diseases, Department of Internal Medicine, University of Kentucky, 800 Rose Street, Lexington, KY 40502 (e<mail: [email protected]). Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0025-7974 DOI: 10.1097/MD.0000000000000016 Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. participating institutions. Of the 97 patients we evaluated, 27 were from Indiana University Health (Indianapolis, IN), 23 were from University of Kentucky (Lexington, KY), 15 from University of Southern California (Los Angeles, CA), 14 from University of Missouri-Kansas City School of Medicine (Kansas City, MO), 12 from Emory University (Atlanta, GA), and 6 were from University of Alabama (Birmingham, AL). Eligibility for inclusion in the analysis required the availability of records and follow-up for at least 1 year. The study was approved by the institutional review boards of each institution. The 97 patients were divided into 2 groups: the physiciandiscontinued suppressive therapy (PD) group (38 patients) and the physician-continued suppressive therapy (PC) group (59 patients). This was not a randomized study. Adherence to antifungal and antiretroviral therapy was determined by the physician’s assessment and human immunodeficiency virus (HIV) RNA levels consistently below 400 c/mL. Adherence in this study referred to both antifungal and antiretroviral therapy. Diagnosis The diagnosis was based upon positive culture, pathology, or antigen testing accompanied by clinical findings compatible with histoplasmosis. Central nervous system (CNS) histoplasmosis was diagnosed in patients who had CNS symptoms and cerebrospinal fluid (CSF) abnormalities suggesting meningeal inflammation, or CNS imaging showing meningeal enhancement, or 1 or more cerebral masses. The laboratory basis for diagnosis of CNS histoplasmosis included positive Histoplasma antigen or antibody from CSF or positive culture or cytologic or histopathologic evidence of Histoplasma in the CSF or brain. Disseminated histoplasmosis was defined as systemic findings such as progressive weight loss, hepatosplenomegaly, extrapulmonary lymphadenopathy, mucosal or skin lesions, anemia, leukopenia, thrombocytopenia, hepatic enzyme elevation, adrenal insufficiency, or demonstration of extrapulmonary involvement by isolating the organism or visualizing it by fungal stain in extrapulmonary tissue. The clinical illness was classified as severe if the patient required management in an intensive care unit, moderate if hospitalization was required without intensive care unit admission, and mild if the illness was managed on an outpatient basis without hospitalization. Laboratory Testing All Histoplasma antigen testing for these patients was performed at MiraVista Diagnostics. The original Histoplasma antigen enzyme immunoassay was modified as a second-generation assay in 2004 to reduce false-positive results, and again in 2007 as a third-generation assay to provide quantification. The main difference in the 2 assays was incorporation of a standard curve permitting quantification in the third-generation assay. The reference range for results considered negative was 0Y0.9 units in the second-generation assay, and none detected in the third-generation assay. The IDSA guideline for stopping therapy included recommendations for both the secondand third-generation assays (2 ng/mL in the third-generation assay and 4 units in the second-generation assay) (Table 1). Twentyone of 84 specimens that were tested before March 2007 that were stored at MiraVista Diagnostics at j20-C were retested in the third-generation assay. If stored specimens were not available, results in the second-generation assay were used. Outcome Relapse of histoplasmosis was defined as recurrence of clinical signs and symptoms compatible with histoplasmosis occurring more than 3 months after the initial episode, accompanied by positive culture, pathology, or increase inHistoplasma antigen. Death was attributed to histoplasmosis if no other cause was determined and laboratory evidence was consistent with active histoplasmosis, including positive culture, increased antigen concentration, or antigen concentration persistently higher than the upper limit of the test (Q39 ng/mL). Remission was classified based on evidence of a period of absence of clinical findings before the relapse of active histoplasmosis. Statistical Analysis For analysis of the relationships of variables between PD and PC patients, univariate analyses were performed using the chi-square test or the Fisher exact test for categorical variables. The Wilcoxon tests were used for continuous variables. SAS version 9.3 (SAS Institute, Cary, NC) was used for statistical analysis. To determine the variables associated with relapse, a multiple logistic regression was performed with the regression modeling the probability of relapse. Variables with a p value G 0.15 in the bivariate analysis and confounders were included in the model. The level of significance was defined as p G 0.05 (2-sided) unless otherwise specified.