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Refractory Mucosal Candidiasis in Advanced Human Immunodeficiency Virus Infection

  1. Carl J. Fichtenbaum1,a,
  2. Susan Koletar6,
  3. Constantin Yiannoutsos2,
  4. Fiona Holland2,a,
  5. John Pottage3,a,
  6. Susan E. Cohn4,
  7. Ann Walawander5,
  8. Peter Frame7,
  9. Judith Feinberg7,
  10. Michael Saag8,
  11. Charles Van der Horst9,
  12. William G. Powderly1, and
  13. Adult AIDS Clinical Trials Group Study Team 816b
  1. 1Washington University School of Medicine, St. Louis, Missouri
  2. 2Harvard School of Public Health, Cambridge, Massachusetts
  3. 3Rush Medical College, Chicago, Illinois
  4. 4University of Rochester School of Medicine, New York
  5. 5Frontier Science Technology Research Foundation, Buffalo, New York
  6. 6Ohio State University School of Medicine, Columbus
  7. 7University of Cincinnati College of Medicine, Ohio
  8. 8University of Alabama-Birmingham School of Medicine, Chapel Hill
  9. 9University of North Carolina School of Medicine, Chapel Hill
  1. 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{at}uc.edu).

  • ↵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.).

 
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Abstract

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.

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Methods

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 CD4+ lymphocyte counts ≤100/mm3. Initially, enrollment was restricted 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 CD4+ lymphocyte counts ≤50/mm3; ACTG 196, a randomized trial of clarithromycin, rifabutin, or both, for preventing MAC disease in patients who had CD4+ 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 CD4+ 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 CD4+ 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 CD4+ 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 developed any signs or symptoms of mucosal candidiasis between visits. Every attempt was made to see patients with active candidiasis between regularly scheduled study visits. Treatment of mucosal candidiasis was not dictated by the study protocol.

Study definitions. Standard ACTG definitions to classify cases of mucosal candidiasis were used as follows. Confirmed mucosal candidiasis was defined by evidence of invasive candidiasis on microscopy (e.g., hyphae or pseudohyphae on a 10% potassium hydroxide slide preparation), in association with a compatible clinical syndrome. Probable mucosal candidiasis was defined by a compatible clinical syndrome and a response to antifungal therapy. A compatible clinical syndrome for oral candidiasis includes the following signs or symptoms: oral pain, dysphagia, white plaques, or erythema. The study team did not specifically distinguish the type of candidiasis (i.e., pseudomembranous vs. erythematous candidiasis) in the database.

A compatible clinical syndrome for esophageal candidiasis includes odynophagia in the presence of oral candidiasis, typical esophageal filling defects (barium swallow test) in the setting of oral candidiasis, or endoscopic visualization of typical plaques. Diagnosis of vaginal candidiasis required documentation of hyphae or pseudohyphae on cytological examination in the presence of a compatible clinical syndrome: vaginal pruritus, vaginal discharge, and/or a maculopapular rash on the vulva. Fluconazole-refractory candidiasis was defined as that which failed to resolve with 14 days of treatment with fluconazole, at a minimum dosage of 200 mg/d. The study chair confirmed all refractory end points. Investigators at study sites were asked to evaluate the participants' medical records to minimize the possibility of missing endpoints.

Continuous use of fluconazole at study enrollment was defined as the administration of ≥50 mg daily or every other day for ≥8 weeks immediately before enrollment. Continuous use during prospective follow-up was defined as ≥50 mg daily or every other day for at least 75% of days since the previous visit. Episodic use of fluconazole at study enrollment was defined as the administration of ≥50 mg/d, for a total of 7 days within the previous 6 months, without meeting the criteria for continuous fluconazole use. Episodic use of fluconazole during prospective follow-up was similarly defined for the period following the last study visit.

Microbiology. Cultures were requested for all patients who developed fluconazole-refractory infection. At the time of diagnosis of fluconazole failure, a sample of serum was collected and frozen at −70°C for testing of fluconazole levels by means of a standard gas-chromatography assay. At 7 study sites, specimens for surveillance cultures for Candida were obtained from the oropharynx and vagina at baseline and every 6 months by swabbing of the buccal mucosa and vaginal mucosa. All cultures for Candida were initially processed at the microbiology laboratories of each study site. All isolates were identified by means of standard National Committee for Clinical Laboratory Standards (NCCLS) methods.

A minimum of 5 colonies were subcultured onto Sabouraud's agar, frozen at −70°C, and sent to the core laboratory at Washington University (St. Louis, MO) for in vitro susceptibility testing by means of a microtiter assay that was based upon the NCCLS standard macrotiter dilution assay [22]. Isolates were regrown on Sabouraud's agar for 24 h at 37°C. Cell suspensions that contained 1 × 106 organisms were diluted in RPMI-1640 media buffered with morpholinepropanesulfonic acid to provide a concentration of 1 × 104 organisms/mL. Fluconazole was diluted in sterile water in concentrations ranging from 0.25 µg/mL to 64 µg/mL. Twenty microliters of each drug dilution was added to 180 µL of organism suspension, yielding a final concentration of 1 × 103 organisms.

Each tray contained 20 isolates (run in duplicate) and 2 growth control isolates (susceptible and resistant). The trays were read at 24 and 48 h of incubation. In vitro susceptibilities were reported as MIC80 values at 48 h. The quality of the in vitro susceptibility testing was confirmed by blind testing of 41 isolates at the Fungus Testing Laboratory at the University of Texas Health Sciences Center at San Antonio. There was concurrence of the in vitro fluconazole susceptibilities, within 1 tube dilution, for 80% of the isolates tested at each laboratory.

Statistical analyses. Statistical analyses were done by use of SAS version 6 (SAS Institute, Cary, NC). For all analyses, P <. 05 was considered significant.

Incidence rates are reported as the number of fluconazole-refractory cases per 100 person-years of follow-up. Univariate analyses of baseline factors associated with the development of fluconazole failure were done for all patients (n = 832), by use of a Cox proportional hazards model. Univariate analyses of on-study (during study) factors associated with the development of fluconazole failure were undertaken by use of a Cox proportional hazards model. Patients were excluded from the on-study model if they did not have the opportunity to develop fluconazole-refractory disease. Specifically, patients were excluded if they did not have fluconazole exposure within 6 months of study enrollment or during the study or had no episodes of mucosal candidiasis within 12 months of study enrollment or during the study (total number of patients excluded from the model, 306).

We correlated the relationship of the development of refractory infection with a unit change in the total dose of fluconazole (in grams), the average daily fluconazole dose (in mg/d), and the duration of fluconazole use (percentage of time for which the drug was received during the study). Each of these parameters was divided into quartiles. The second, third, and fourth quartiles were evaluated against the lowest quartile. A time-dependent covariate for continuous or episodic versus no use of fluconazole was also considered as a risk factor for the development of fluconazole failure.

A backward model-selection algorithm was used to determine the final multivariate model. Variables with P ≤ .20 were entered into the multivariate model. At each step, the least-significant variable was removed, and selection continued until all retained covariates reached significance at the 5% level.

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Results

A total of 842 patients were enrolled at 25 ACTG study centers. Ten patients were excluded from the final analysis because of a history of fluconazole-refractory infection.

Baseline characteristics of the study population are shown in table 1. The incidence and prevalence of on-study episodes of candidiasis are shown in figure 1. Thirty-six patients had a confirmed episode of fluconazole-refractory infection: 35 had oral candidiasis and 1 had esophageal candidiasis. There were no confirmed incident episodes of fluconazole-refractory vaginal candidiasis. The estimated incidence of fluconazole failure was 4.2 per 100 person-years of follow-up (n = 832). The estimated proportion of fluconazole failures within 1 year was 4.7% (95% CI, 3.1%–6.3% [Kaplan-Meier estimate of the distribution of candidiasis-free survival]).

Twenty-nine of 36 patients (81%) had culture specimens obtained at the time of failure. Candida albicans was recovered from 28 (97%), either as the sole isolate (n = 24) or with either Candida krusei (n = 2) or Candida glabrata (n = 2). One patient (3%) had only C. glabrata isolated. Findings of in vitro susceptibility testing against fluconazole were available for 26 (90%) of 29 patients. Sixty-nine percent of the patients (n = 18) had an isolate recovered for which the MIC80 of fluconazole was ≥64 µg/mL; 12% (n = 3) had an isolate recovered with an MIC80 of 32 µg/mL; 15% (n = 4) had an isolate recovered with an MIC80 of 16 µg/mL; and 4% (n = 1) had an isolate recovered with an MIC80 ≤8 µg/mL.

A random serum fluconazole level was available for 9 (25%) of 36 patients. All patients tested had a measurable amount of fluconazole when their first episode of refractory candidiasis was diagnosed (mean level, 10.4 µg/mL; range, 1.5–19.6 µg/mL). One patient with clinically refractory candidiasis due to a fluconazole-susceptible organism (MIC80, ≤8 µg/mL) had a random level of fluconazole of 4.3 µg/mL.

Univariate analysis of baseline factors demonstrated that the use of prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) and the more frequent occurrence of prior episodes of oral or esophageal candidiasis were significantly associated with the development of fluconazole-refractory infection (table 2). There was a trend toward a higher rate of fluconazole failure among patients with a history of MAC disease. Univariate analysis of on-study factors demonstrated that longer duration of use and higher daily average doses of fluconazole were significantly associated with the development of refractory infection (table 3).

In a time-updated analysis, the continuous use of fluconazole was significantly associated with fluconazole failure when compared with no use (relative risk [RR], 5.60; 95% CI, 1.69–18.51; P =.005, Cox proportional hazards model). In contrast, there was no significant association between the intermittent use of fluconazole (vs. no use) and the development of fluconazole failure (RR, 2.94; 95% CI, .76–11.38; P =.12, Cox proportional hazards model). In addition, the total dose of fluconazole was not significantly associated with the development of refractory infection.

In the multivariate model of baseline factors, the following were significantly associated with the development of fluconazole-refractory infection: use of TMP-SMZ (RR, 2.47; 95% CI, 1.08–5.67; P = .032, Cox proportional hazards model); occurrence of 1–3 episodes (vs. none) of esophageal candidiasis during the 12 months before enrollment (RR, 3.096; 95% CI, 1.34–7.15; P = .008, Cox proportional hazards model); occurrence of 1–3 episodes (vs. none) of oral candidiasis within 12 months of study enrollment (RR, 2.76; 95% CI, 1.02–7.49; P = .046, Cox proportional hazards model); and occurrence of >3 episodes (vs. none) of oral candidiasis within 12 months of study enrollment (RR, 4.93; 95% CI, 1.75–13.87; P = .003, Cox proportional hazards model). The final multivariate model for both the baseline and on-study factors is presented in table 4.

Treatment-response information for the initial episode of fluconazole failure was available for 28 patients (78%). Fifteen (54%) continued receiving fluconazole after clinical failure. Of those 15, 9 had their fluconazole daily dose increased to ≥400 mg, but the condition of 6 (67%) did not improve with higher doses. Four patients continued receiving fluconazole at a dosage of 200 mg daily: the condition of 2 of these patients improved after a minimum of 8 weeks of therapy but not for the other 2. The remaining 2 patients who took fluconazole used an unspecified dose along with clotrimazole, and the condition of both eventually improved. Six patients (21%) switched to itraconazole capsules, which resulted in improvement for 3.

The condition of all 4 patients who received parenteral amphotericin B improved. One patient responded to treatment with 1% gentian violet and another to clotrimazole troches. One patient stopped all antifungal therapy and had persistent thrush until death. Relapse of FROC occurred in 50% of those with an initial response.

Twenty patients (55%) with FROC died during the study. The median duration of survival was 32.6 weeks after the diagnosis of refractory candidiasis. This was shorter than for patients whose diagnosis was a first episode of PCP (n = 18; 82.6 weeks), MAC disease (n = 25; 51.9 weeks), or CMV disease (n = 38; 42.6 weeks).

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Discussion

Fluconazole-refractory oral candidiasis in persons with HIV infection was first reported in 1991 [3, 4]. Because this entity was incompletely described and understood, this study was designed to characterize the epidemiology and outcome of this emerging complication of AIDS. An important goal of this study was to describe the incidence of FROC in persons with advanced HIV infection so that a randomized strategy trial could be designed to determine the best use of fluconazole for mucosal candidiasis. We also wanted to determine whether consistent use of fluconazole (daily or every other day) or treatment of specific episodes was more frequently associated with fluconazole failure. This information might have a potential impact on fluconazole-prescribing patterns.

The definition of fluconazole-refractory infection has varied in the literature [2–17]. In the absence of a consensus definition, the ACTG developed a working definition of clinical failure. The goal was to develop a definition that would correlate with clinical outcomes. The definition of failure developed in ACTG 816 did, in fact, correlate with reduced in vitro susceptibility to fluconazole and poor clinical outcome. For nearly all of the patients (96%) from whom an isolate was available for in vitro testing, susceptibility values were in the resistant or dose-responsive category [21].

Most patients had a poor response to higher doses of fluconazole (these failed for 6 of 9). In addition, more than one-half of the patients with refractory infection died, after surviving for a median of 32.6 weeks. Thus, failure to respond to fluconazole at a dosage of ≥200 mg/d for 14 days appears to be a useful clinical definition for refractory infection.

The incidence of FROC in our population with advanced HIV infection was 4.2 events per 100 person-years. All but 1 of these cases was restricted to the oral cavity. There were no incident cases of refractory vaginitis. The prevalence of refractory vaginal infection was 2% (2/95), with both cases occurring before study enrollment. The incidence of FROC compares with the observations of Schuman et al. [23], who studied 323 women in a placebo-controlled randomized trial of weekly fluconazole prophylaxis. In that trial, 13 women (4%) developed fluconazole-refractory infection.

There have been several single-center retrospective studies of the incidence of FROC. Most involved <200 patients, and the incidence varied from 5.8% to 14% [7, 9, 11, 12]. Thus, although some of these initial reports of retrospective studies suggested that the incidence of FROC might be substantially higher, the annual incidence is probably not >5%. The incidence of fluconazole-refractory esophagitis and vaginitis appears to be much lower.

We found a number of factors that were significantly associated with the development of FROC. One of the most important host factors described by others is profound immunosuppression [3–7, 11–14, 17, 24]. Few cases of fluconazole failure involve persons with CD4+ lymphocyte counts >50/mm3. Our study was largely restricted to individuals with CD4+ lymphocyte counts <50/mm3, which limited our ability to evaluate this factor. We did not detect a correlation between the absolute value of the baseline CD4+ lymphocyte count and the development of FROC. Because HIV-1 levels were not routinely measured during the time of the study, we do not have information on whether there is a correlation between viral load and the development of FROC.

Another important risk factor is the exposure to antifungal medications over time. We found that higher daily doses of fluconazole and longer periods of usage both correlated with increasing risk of FROC. The risk of developing FROC was as much as 20 times higher for persons who had used ≥100 mg of fluconazole daily or every other day than for those with minimal or no exposure (P < .01). Furthermore, near-constant use of fluconazole (86%–100% of the time on-study), compared with minimal use (0%–11% of the time), conferred a 9-fold higher risk (P <.01).

Maenza et al. [17] reported a longer median duration of exposure to antifungal therapy (419 vs. 118 days; P < .001) and, specifically, to systemic azole therapy (272 vs. 14 days; P < .001) among persons who had FROC than among matched control subjects. Similarly, others have demonstrated that the risk of FROC increases with higher doses of fluconazole [11]. Unlike Heald et al. [25], we did not find that episodic treatment with fluconazole was associated with the emergence of FROC.

Finally, several other factors were associated with the development of FROC. Frequently recurring oral or esophageal candidiasis at baseline and the chronic use of TMP-SMZ as prophylaxis for PCP were significantly associated with the development of FROC. It is possible that the long-term use of antibiotics, such as TMP-SMZ, might alter the flora of the oral cavity and predispose patients to more frequent episodes of candidiasis. This, in turn, may predispose patients to FROC.

In addition, most of our patients (92%) with FROC, whose isolates were available for in vitro susceptibility testing, were resistant to fluconazole (MIC80, ≥32 µg/mL). This is consistent with other observations [26–28]. Most of the refractory cases were associated with the recovery of C. albicans. The isolation of non-albicans Candida species from persons with FROC was uncommon, despite heavy exposure to fluconazole. We observed a trend toward the development of FROC in patients with a history of MAC disease, which may well be related to the chronic use of broad-spectrum antibiotics for the management of disseminated MAC disease. There was no correlation between the development of FROC and the number of previous opportunistic illnesses, use of antiretrovirals (data not shown), sex, or the prior occurrence of PCP or CMV disease.

The morbidity and mortality associated with FROC were significant. Response to therapy was suboptimal, but parenteral amphotericin B was the most potent. Relapse of FROC occurred in 50%. Median survival time from diagnosis of FROC to death was only 32.6 weeks, which was much shorter than the median survival time after the diagnosis of MAC disease, CMV disease, or PCP. Our observations on the efficacy of treatment for FROC are comparable with those in recent reports on controlled trials of itraconazole solution and amphotericin B oral solution, with response rates of 44%–65% in several studies [29–33]. The relapse rate was 50% in 1 trial of itraconazole solution [32]. Finally, Koletar et al. have reported a median survival time of 26 weeks among 22 patients with FROC [34]. Clearly, the development of FROC portends a very poor prognosis.

This study has important implications for patients with advanced HIV disease who are using fluconazole. Our study indicates that daily or every-other-day use of fluconazole is much more frequently associated with the development of FROC. This finding, along with the lack of any proven survival benefit from fluconazole prophylaxis, suggests that fluconazole is best used episodically, although a randomized, controlled trial would be required to confirm this hypothesis [35]. It may be prudent to avoid the continuous use of fluconazole, except for patients with invasive fungal disease such as cryptococcal meningitis, until the results of a randomized clinical trial become available.

This study was designed and conducted before the use of potent combination antiretroviral therapy and the measurement of plasma HIV-1 RNA levels became routine. The incidence of opportunistic infections, including FROC, has declined with the use of HAART. Nevertheless, the findings in this study may still be useful, since there are many patients with advanced HIV infection who are not taking potent antiretroviral therapy and are still using fluconazole.

Higher plasma HIV-1 RNA levels are a good predictor of oropharyngeal colonization with Candida [36, 37]. Whether this marker can predict the occurrence of FROC is not known and was not evaluated in this study. Finally, it is not known whether these results will apply to individuals with low CD4+ lymphocyte counts who experience virologic failure of antiretroviral therapy.

In conclusion, fluconazole-refractory oral candidiasis is a potentially important problem for persons with advanced HIV infection. The clinical definition of fluconazole-refractory infection developed in this study correlates well with reduced in vitro susceptibilities and poor clinical outcomes. The clinical factors associated with the occurrence of fluconazole-refractory candidiasis include prolonged exposure to fluconazole, use of higher daily doses of fluconazole, more frequent episodes of oral or esophageal candidiasis, chronic use of TMP-SMZ, and, possibly, the prior occurrence of MAC disease. It is likely that several of these factors are required for the development of fluconazole-refractory infection.

Treatment of fluconazole-refractory infection is problematic, with response rates typically <65% for oral therapy. Parenteral amphotericin B remains the most potent therapy. Relapses are common, and maintenance therapy is usually required. The prognosis is extremely poor for persons who develop fluconazole-refractory oral candidiasis if they do not receive effective antiretroviral medications.

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Adult AIDS Clinical Trials Study Group Team

The following is a list of additional participating sites and individuals who made significant contributions to the design and conduct of the study: Linda Brasington, Carol Greisberger, Ross Hewitt, and Richard Reichman (University of Rochester); Tom Stiffler, Mike Conklin, and Michael Klebert (Washington University); Robert J. Fass, Michael F. Para, and Judith L. Neidig (Ohio State University); Harold Kessler and Robert Murphy (Rush—Presbyterian St. Luke's Medical Center); Joseph Pulvirenti (Cook County Hospital); Ken Skahan, Steve Kralovic, Diane Daria, and Pam Daniel (University of Cincinnati); Dorcas Baker, Melody Higgins, and Linda Apuzzo (Johns Hopkins University); Eden Akavia, Melissa Vidic, Victoria Rosenwald, and Jane Dowling (New York University); Thomas Hooton, Ann Collier, Becky Royer, and Karen Novak (University of Washington); Steven C. Johnson, Nancy Madinger, Suzanne Fiorillo, and Caitlin Magee (University of Colorado Health Sciences Center); Katherine W. Merrill, Kathleen E. Squires, Donna Davis, and Robert H. Hill (University of Alabama at Birmingham); John Black, Mitchell Goldman, Kris Todd, and Heather Nixon (Indiana University Hospital); Barbara Gripshover, Henry Krzemien, Robert Sprosty, and Ronald Johnson (Case Western University); Monica Millard, Lyle Oshita, Debra Ogata-Arakaki, and Amy Kindrick (University of Hawaii); Connie Kapeluck (Harbor University of California Los Angeles Medical Center); Susan Swindells, Jane Hamer, and Sharon Richard (University of Nebraska Medical Center); J. Jacobson, K. Luykx, and P. Gerits (Mount Sinai Medical Center); V. Koslowski and Craig Kessler (region II/III under the National Hemophilia Foundation); and Donald E. Craven and Diane Joyce Otis (Boston Medical Center).

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Figures and Tables

Figure 1
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Figure 1

Incidence and prevalence of mucosal candidiasis. Nos. at the top of each bar represent the incidence (black bars) and prevalence (white bars) of episodes of mucosal candidiasis. The y axis measures the incidence (Y1 bar, black) in 100 person-years and prevalence (Y2 bar, white) per 100 persons. The 95% confidence intervals (CIs) for incident disease are as follows: oral candidiasis, 41–52 per 100 person-years; esophageal candidiasis, 6.9–10.9 per 100 person-years; and vaginal candidiasis, 2.3–13 per 100 person-years. The 95% CIs for prevalent disease are as follows: oral candidiasis, 61–71 per 100 patients; esophageal candidiasis, 5.7–19.7 per 100 patients; and vaginal candidiasis, 9.3–12.5 per 100 patients.

Table 1
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Table 1

Baseline characteristics of the study population (n = 832) of patients with advanced HIV infection.

Table 2
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Table 2

Univariate analysis of time to fluconazole failure, by use of baseline variables.

Table 3
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Table 3

Univariate Cox analyses of on-study risk factors for fluconazole failure.

Table 4
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Table 4

Multivariate model for baseline and on-study factors.

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Acknowledgments

The ACTG 816 Study Team thanks all of the patients for volunteering their time. We also thank Samantha Mawhinney, Dafeng Chen, and Laura Mahon for their invaluable assistance.

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Footnotes

  • ↵b List of additional contributors appears at the end of text.

  • 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.

  • Received May 4, 1999.
  • Revision received August 17, 1999.
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  1. Clin Infect Dis. (2000) 30 (5): 749-756. doi: 10.1086/313765
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