Refractory Mucosal Candidiasis in Advanced Human Immunodeficiency Virus Infection

749 Refractory Mucosal Candidiasis in Advanced Human Immunodeficiency Virus Infection Carl J. Fichtenbaum,1,a Susan Koletar,6 Constantin Yiannoutsos,2 Fiona Holland,2,a John Pottage,3,a Susan E. Cohn,4 Ann Walawander,5 Peter Frame,7 Judith Feinberg,7 Michael Saag,8 Charles Van der Horst,9 and William G. Powderly1 for the Adult AIDS Clinical Trials Group Study Team 816b From the 1Washington University School of Medicine, St. Louis, Missouri; 2Harvard School of Public Health, Cambridge, Massachusetts; 3Rush Medical College, Chicago, Illinois; 4University of Rochester School of Medicine, New York, and 5Frontier Science Technology Research Foundation, Buffalo, New York; 6Ohio State University School of Medicine, Columbus, and 7University of Cincinnati College of Medicine, Ohio; 8University of Alabama–Birmingham School of Medicine; 9 University of North Carolina School of Medicine, Chapel Hill We conducted a multicenter, prospective study of the risk factors, natural history, and outcome of fluconazole-refractory mucosal candidiasis (FRMC) in 832 persons with advanced human immunodeficiency virus (HIV) infection (median CD4 cell count, 14/mm3) during 1994–1996. FRMC was defined as mucosal candidiasis that failed to resolve despite 14 days of therapy with daily doses (>200 mg) of fluconazole. Thirty-six persons (4.3%) had FRMC (35, oral; 1, esophageal), for an incidence of 4.2 per 100 person-years (859.7 total years of follow-up). In a multivariate model, the use of trimethoprim-sulfamethoxazole within 6 months of enrollment (relative risk [RR], 2.39; P = .04 ) and the use of fluconazole daily or every other day (RR, 5.64; P = .004) were significantly associated with the development of FRMC. The median survival after the development of FRMC was 32.6 weeks. In conclusion, the annual incidence of FRMC was !5%. Refractory candidiasis was a poor prognostic indicator. Daily or every-other-day use of fluconazole was associated with the development of refractory infection. In the era before the use of highly active antiretroviral therapy (HAART), mucosal candidiasis was a frequent problem for persons with HIV infection [1, 2]. Typically, this disease was relatively easy to manage with topical or systemic antifungal therapy. Case reports of fluconazole-refractory oral candidiasis (FROC) began to appear in 1991, after the use of fluconazole for the treatment of and prophylaxis for many fungal infections became widespread [3–21]. These early reports documented that FROC was often difficult to treat and frequently required the use of parenteral amphotericin B. In published reports of several small retrospective series, the incidence of FROC ranged from 5% to 14% [7, 9, 11, 12]. The risk factors, natural history, and outcome of FROC were not clearly described. Although the use of fluconazole was associated with the development of FROC, it was not clear whether episodic or continuous use was more likely to be associated with the development of refractory infection. Therefore, we designed a prospective observational study to determine the incidence, risk factors, and outcome of fluconazole-refractory mucosal candidiasis in patients with advanced HIV infection. It is important to note that this study was conducted before the use of HAART and the measurement of plasma HIV-1 RNA levels became routine. Methods Received 4 May 1999; revised 17 August 1999; electronically published 28 April 2000. Grant support: National Institutes of Health (AI-25903). The institutional review board at each participating site approved the study, and written informed consent was obtained from all patients. a Current affiliations: University of Cincinnati College of Medicine, Cincinnati, Ohio (C.F.); Department of Mathematics and Statistics, Lancaster University, Lancaster, United Kingdom (F.H.); Vertex Pharmaceuticals, 130 Waverly Street, Cambridge, Massachusetts (J.P.). b List of additional contributors appears at the end of text. Reprints or correspondence: Dr. Carl Fichtenbaum, University of Cincinnati Medical Center, Holmes Division, Infectious Diseases Center, Eden and Bethesda Avenues, Cincinnati, OH 45267-0405 (carl.fichtenbaum@uc .edu). Clinical Infectious Diseases 2000; 30:749–56 q 2000 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2000/3005-0001$03.00 Design. AIDS Clinical Trials Group (ACTG) Study 816 was a prospective observational study of fluconazole-refractory candidiasis in persons with advanced HIV infection. The primary objectives were to describe the incidence, risk factors, and outcome of clinical resistance to fluconazole of mucosal candidiasis. A secondary objective was to compare the median duration of survival of patients with FROC, Pneumocystis carinii pneumonia (PCP), disseminated Mycobacterium avium complex (MAC) disease, and cytomegalovirus (CMV) end-organ disease. The study was conducted during 1994–1996, before the widespread use of HAART. Study population. Patients were eligible for enrollment if they had documented evidence of HIV infection or AIDS (as defined by the Centers for Disease Control and Prevention) and CD41 lymphocyte counts <100/mm3. Initially, enrollment was restricted 750 Fichtenbaum et al. to participants in 3 concurrent ACTG trials: ACTG 193, a study of combination nucleoside and nonnucleoside reverse transcriptase inhibitors for patients who had previously received nucleosides and had CD41 lymphocyte counts <50/mm3; ACTG 196, a randomized trial of clarithromycin, rifabutin, or both, for preventing MAC disease in patients who had CD41 lymphocyte counts <50/mm3; and ACTG 204, a randomized trial of 3 doses of acyclovir or valacyclovir for preventing CMV end-organ disease in patients who had CD41 lymphocyte counts <100/mm3 who were seropositive for CMV antibodies. Enrollment for ACTG 816 began in May 1994. After April 1995, the study was amended to allow for enrollment of any patient with a CD41 lymphocyte count <50/mm3 and no history of fluconazole-refractory mucosal candidiasis. The study was closed to enrollment in August 1995, and follow-up continued for 1 year. Study procedures. All patients had their CD41 lymphocyte counts and complete medical histories determined and oropharyngeal examinations performed at baseline. Women with symptoms of vaginitis also underwent gynecologic examinations. Medical records for the 12 months before study enrollment were also routinely obtained to confirm diagnoses. From May 1994 through April 1995, patients were followed according to the study schedule of their parent trial (ACTG 193, 196, or 204). Follow-up visits were either every 8 weeks or every 12 weeks. After April 1995, all patients were followed every 8 weeks. At each study visit, medications used and interval medical histories were recorded. A targeted physical examination was performed. Women who reported any vaginal symptoms also underwent gynecologic examinations. Patients were instructed to call the study site if they deve (...truncated)