Weekly Fluconazole for the Prevention of Mucosal Candidiasis in Women with HIV Infection

A Randomized, Double-Blind, Placebo-Controlled Trial

  1. Paula Schuman, MD, MPH;
  2. Linnea Capps, MD, MPH;
  3. Grace Peng, MS;
  4. Jose Vazquez, MD;
  5. Wafaa El-Sadr, MD, MPH;
  6. Anne I. Goldman, PhD;
  7. Beverly Alston, MD;
  8. C. Lynn Besch, MD;
  9. Anita Vaughn, MD;
  10. Melanie A. Thompson, MD;
  11. Malik N. Cobb, RPA-C;
  12. Thomas Kerkering, MD; and
  13. Jack D. Sobel, MD
  1. The Terry Beirn Community Programs for Clinical Research on AIDS. Acknowledgments: The authors thank Barbara Brizz, Carroll Child, Marjorie Dehlinger, Lawrence Deyton, Kathy Canady, Perry Eisman, Betsy Finley, and Dianne Murphy; the former DAIDS Medical Officer, Joyce Korvick; and the laboratory technologist, Kathleen M. Furness. Requests for Reprints: Paula Schuman, MD, MPH, Division of Infectious Diseases, Wayne State University, Harper Professional Building, 4160 John R Road, Suite 2140, Detroit, MI 48201. Current Author Addresses: Drs. Schuman, Vazquez, and Sobel: Division of Infectious Diseases, Wayne State University, Harper Professional Building, 4160 John R Road, Suite 2140, Detroit, MI 48201.
     
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    Abstract

    Background: Candidiasis is a frequent complication of infection with the human immunodeficiency virus (HIV); however, few data exist about the natural history, prevention, and treatment of mucosal candidiasis in women.

    Objective: To evaluate the safety and effectiveness of weekly fluconazole prophylaxis for mucosal candidiasis in women infected with HIV.

    Design: Randomized, double-blind, placebo-controlled trial.

    Setting: 14 sites participating in the Community Programs for Clinical Research on AIDS (CPCRA).

    Patients: 323 women with HIV infection and CD4+ cell counts of 300 cells/mm3 or less.

    Intervention: 200 mg of fluconazole per week or placebo. Open-label fluconazole for candidiasis prophylaxis was permitted after two oropharyngeal or vaginal episodes or one esophageal episode.

    Measurements: Development of mucosal candidiasis, clinical and in vitro resistance of Candida species to fluconazole, survival, and adverse events.

    Results: After a median follow-up of 29 months, 72 of 162 patients receiving fluconazole and 93 of 161 patients receiving placebo had at least one episode of candidiasis (relative risk [RR], 0.56 [95% CI, 0.41 to 0.77]; P < 0.001). Weekly fluconazole was effective in preventing oropharyngeal candidiasis (RR, 0.50 [CI, 0.33 to 0.74]; P < 0.001) and vaginal candidiasis (RR, 0.64 [CI, 0.40 to 1.00]; P = 0.05) but not esophageal candidiasis (RR, 0.91 [CI, 0.48 to 1.72]; P > 0.2). Relative risks were similar for women who had a history of mucosal candidiasis (RR, 0.51 [CI, 0.35 to 0.75]) and those who did not (RR, 0.69 [CI, 0.35 to 1.34]). Absolute risk reduction for patients with a history of infection was 25.6 per 100 person-years, which is more than twice the reduction of 11.2 per 100 person-years seen in patients with no history of infection. This difference reflects the higher risk of patients who previously had an infection. Candida albicans was not usually resistant to fluconazole in vaginal specimens in clinical or in vitro settings; such resistance occurred in less than 5% of patients in each group.

    Conclusions: Weekly fluconazole (200 mg) seems to be safe and effective in preventing oropharyngeal and vaginal candidiasis. This regimen has a useful role in the management of HIV-infected women who are at risk for recurrent mucosal candidiasis.

    The demographic characteristics of the human immunodeficiency virus (HIV) epidemic in the United States have changed markedly in recent years. In 1994, 18% of new cases of acquired immunodeficiency syndrome (AIDS) occurred in women [1]; AIDS is now the third leading cause of death in women of reproductive age [2].

    Candidiasis is a frequent complication of HIV infection [3-5]. The risk for oropharyngeal and esophageal candidiasis increases as the immune system becomes more suppressed. Vaginal candidiasis is also common in HIV-infected women [6, 7]. Because few HIV-infected women have been enrolled in clinical trials of therapy for and prophylaxis of fungal infections, few data have been recorded on the natural history, prevention, and treatment of mucosal candidiasis in women.

    Fluconazole, a broad-spectrum systemic antifungal agent, has been used effectively for the treatment of candidiasis in patients with HIV infection or AIDS and may result in a more rapid clinical and mycologic response than other azoles [8]. Although several regimens of fluconazole have been shown to prevent candidiasis (including recurrent episodes in persons with HIV infection), routine prophylaxis with fluconazole has not been recommended because of cost; the possible emergence of resistant Candida species; and drug interactions with non-sedating antihistamines, warfarin, phenytoin, oral hypoglycemic agents, rifampin or rifabutin, and hydrochlorothiazide [9-11].

    The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) initiated this study in HIV-infected women to evaluate the effectiveness and safety of weekly fluconazole for the prevention of mucosal candidiasis and to detect alterations in vaginal colonization by Candida species [12]. A substudy was also done to investigate in vitro resistance to Candida organisms.

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    Methods

    Study Sample

    Patients were enrolled in the Women's Fungal Study (CPCRA 010) at 14 sites that were participating in the CPCRA [12]. The CPCRA is a consortium of community-based sites that provide primary health care to patients who are infected with HIV. Potentially eligible patients were identified by physicians who were participating in the consortium.

    Female patients with HIV infection who were 13 years of age or older were eligible if their CD4+ cell count did not exceed 300 cells/mm3 or 20% of their total lymphocyte count. Patients were excluded if they had a history of Candida esophagitis, were receiving systemic antifungal agents, had a known intolerance of azoles, or were pregnant or lactating. The protocol was approved by the internal review board at each site. Informed consent was obtained from all patients before they were assigned to a study group.

    Study Design

    In this double-blind trial, patients were randomly assigned to receive weekly fluconazole or placebo using a permuted block scheme with randomly mixed block sizes of two and four. Randomization was stratified by CPCRA site and was done through the CPCRA statistical center. The target sample size (400 patients) and study duration (18 months) were chosen to ensure that there would be 80% power to detect a 50% difference in the rate of episodes of candidiasis between groups with a two-sided P value of 0.05. We extended the follow-up period to obtain more information on clinical and in vitro resistance.

    Treatment Regimens

    Fluconazole was provided in 100-mg capsules; patients received 200 mg of fluconazole per week or placebo. This dosage was used because pharmacologic studies by Houang and colleagues [13] indicated that therapeutic concentrations of fluconazole greater than the median minimal inhibitory concentration (MIC) of Candida albicans were found in vaginal secretions and tissues for 96 hours after a fluconazole dose of 150 mg.

    Open-label daily fluconazole for prophylaxis was permitted after two episodes of oropharyngeal or vaginal candidiasis or one episode of esophageal candidiasis (that is, prophylaxis failure). The relative severity of the candidiasis was considered in defining prophylaxis failure. Therapy with the study drug was continued during episodes of oropharyngeal and vaginal candidiasis but not during episodes of esophageal candidiasis. Ongoing use of systemic antifungal agents required withdrawal of the study drug. Topical antifungal agents were recommended for the treatment of oropharyngeal and vaginal candidiasis; fluconazole was recommended for esophageal candidiasis.

    End Points

    Episodes of candidiasis were reviewed by a committee that was blinded to treatment group. Several major clinical end points were specified: 1) first episode of confirmed vaginal candidiasis, confirmed oropharyngeal candidiasis, or confirmed or probable esophageal candidiasis; 2) prophylaxis failure, defined as the first episode of confirmed or probable esophageal candidiasis or the second episode of confirmed vaginal or oropharyngeal candidiasis; and 3) confirmed or probable clinical resistance to fluconazole.

    Esophageal candidiasis was confirmed by histologic or cytologic evidence on microscopy or evidence of candidiasis on gross endoscopic inspection or at autopsy. Patients were considered to have had a probable episode of esophageal candidiasis if they had recent onset of dysphagia or odynophagia and had either a confirmed diagnosis of oropharyngeal candidiasis or a response to antifungal therapy.

    Oropharyngeal or vaginal candidiasis was confirmed by a positive culture for Candida species in the presence of two or more clinical signs or symptoms. Patients were considered to have had a probable episode of mucosal candidiasis if 1) the culture was positive and they had one clinical sign or symptom [other than white exudates for oropharyngeal candidiasis], 2) a potassium hydroxide preparation was positive and they had two or more clinical signs or symptoms, or 3) they responded to antifungal therapy and had two or more signs or symptoms.

    Confirmation of clinical resistance to fluconazole required all of the following: 1) confirmed or probable esophageal candidiasis, confirmed vaginal candidiasis, or confirmed oropharyngeal candidiasis; 2) no response to a previous course of antifungal therapy and the need for high-dose therapy with systemic azoles or intravenous amphotericin B; and 3) no other identifiable cause of the symptoms. The patients were considered to have had probable clinical resistance if the first two criteria were met but other causes for the symptoms could not be ruled out.

    Adverse events were graded on a five-point scale (I through V). We recorded events that were at least grade IV, that were not caused by the progression of HIV infection, and that led to discontinuation of treatment while patients were receiving the study medication and for 8 weeks thereafter.

    Follow-up

    The trial ended on 30 November 1995, which was 22 months after the last patient was randomly assigned. The median length of follow-up was 29 months. Every 3 months, we ascertained symptoms of candidiasis, collected a vaginal specimen for yeast culture, and documented concomitant treatments and new HIV-related diagnoses. Liver function tests were done and CD4+ cell counts were measured every 6 months.

    Substudy of in Vitro Resistance to Fluconazole

    A substudy examining in vitro resistance to fluconazole (CPCRA 029) was started 1 year after the primary study began. After patients were enrolled, vaginal specimens that were obtained at scheduled follow-up visits every 3 months were analyzed for susceptibility to five antifungal agents. Isolates that had been obtained for other end points of the primary study were also analyzed. We used microtiter methods for in vitro susceptibility testing in accordance with National Committee for Clinical Laboratory Standards [14]. In vitro resistance to fluconazole was defined as an MIC of 16 µg/mL or less at 48 hours.

    Statistical Analysis

    Participating investigators were blinded to interim results. Treatment groups were compared according to each patient's original assignment (intention-to-treat analysis); the comparison groups consisted of patients who received weekly fluconazole and patients who received placebo until prophylaxis failure, at which time daily fluconazole could be prescribed at the clinician's discretion.

    Analyses were stratified by CPCRA site in accordance with the randomization method. Baseline comparability was assessed using the Mantel-Haenszel chi-square or stratified analysis of variance [15, 16]. For clinical end points and adverse events, time-to-event methods (including Kaplan-Meier estimation, log-rank tests, and proportional hazards regression models) were used to compare treatment groups [17-19]. We also compared two-sided P values and 95% CIs for relative risks (RRs) of fluconazole with those of placebo. Natural history analyses could be done because our control group received placebo. For such analyses, a proportional hazards regression model was used to investigate the independent influence of the following baseline variables on risk for candidiasis: ethnic group, injection drug use, CD4+ cell count, history of mucosal candidiasis, presence of AIDS, prophylaxis for Pneumocystis carinii pneumonia, antiretroviral treatment, and result of vaginal yeast culture at baseline.

    Vaginal specimens were collected every 3 months and analyzed for colonization by Candida species using a model for longitudinal binary data; findings are summarized with relative odds estimates for fluconazole compared with placebo [20]. All analyses were done using SAS software (SAS Institute, Cary, North Carolina).

    The National Institute of Allergies and Infectious Diseases (NIAID) supported the clinical sites and statistical center responsible for gathering and analyzing the data. Staff members from NIAID were also part of the protocol team but had no role in the decision to publish the results of the study.

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    Results

    Study Sample

    Between May 1992 and January 1994, 323 patients were enrolled in CPCRA 010; 162 were randomly assigned to receive fluconazole and 161 to matching placebo. Characteristics at baseline were well balanced (Table 1).

    View this table:
    Table 1. Baseline Characteristics by Treatment Group*

    Ninety-five percent of surviving patients receiving fluconazole and 90% receiving placebo attended a follow-up visit within 6 months of the end of the study. Survival status was known at the end of the study for 98% of patients in each group.

    Treatment Course

    Patients received fluconazole for a median of 17 months and placebo for a median of 10 months. Therapy with study medication was permanently discontinued for 70% of patients receiving fluconazole and 83% of patients receiving placebo (P < 0.001 by log-rank test).

    Seventy-six patients received open-label fluconazole; 29 had been assigned to receive fluconazole (18% of the group) and 47 had been assigned to receive placebo (29% of the group) (P = 0.01 by log-rank test). Ten of the 29 patients in the fluconazole group and 28 of the 47 in the placebo group received open-label fluconazole after prophylaxis failure. Exposure to fluconazole (blinded or open-label) for prophylaxis substantially differed between the fluconazole group (78% of the trial time) and the placebo group (16% of the trial time).

    Clinical End Points

    Seventy-two of 162 patients receiving fluconazole and 93 of 161 patients receiving placebo had at least one episode of candidiasis (RR, 0.56; P < 0.001) (Table 2 and Figure 1). Weekly fluconazole was effective in preventing vaginal candidiasis (RR, 0.64; P = 0.05) and oropharyngeal candidiasis (RR, 0.50; P < 0.001) (Figure 2 and Figure 3). However, the effect of weekly fluconazole on the prevention of esophageal candidiasis could not be established because only 38 episodes (8 confirmed and 30 probable) occurred.

    View this table:
    Table 2. Rates of Candidal Events by Treatment Group
    Figure 1. Solid lines indicate patients receiving weekly fluconazole; dashed lines indicate patients receiving placebo. The number of patients at risk at 6, 12, 18, 24, and 30 months for first mucosal event are 127, 106, 91, 74, and 43 in the fluconazole group and 103, 77, 65, 56, and 27 in the placebo group, respectively. Corresponding numbers for prophylaxis failure are 143, 121, 107, 91, and 56 for the fluconazole group and 135, 108, 86, 75, and 42 for the placebo group, respectively.
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    Figure 1. Solid lines indicate patients receiving weekly fluconazole; dashed lines indicate patients receiving placebo. The number of patients at risk at 6, 12, 18, 24, and 30 months for first mucosal event are 127, 106, 91, 74, and 43 in the fluconazole group and 103, 77, 65, 56, and 27 in the placebo group, respectively. Corresponding numbers for prophylaxis failure are 143, 121, 107, 91, and 56 for the fluconazole group and 135, 108, 86, 75, and 42 for the placebo group, respectively. Kaplan-Meier estimates of the percentage of women who remained free of mucosal candidiasis and prophylaxis failure by treatment group.
    Figure 2. Solid line indicates patients receiving weekly fluconazole; dashed line indicates patients receiving placebo. The numbers of patients at risk at 6, 12, 18, 24, and 30 months for confirmed vaginal candidiasis are 143, 126, 113, 91, and 52 in the fluconazole group and 132, 108, 90, 72, and 40 in the placebo group, respectively.
    View larger version:
    Figure 2. Solid line indicates patients receiving weekly fluconazole; dashed line indicates patients receiving placebo. The numbers of patients at risk at 6, 12, 18, 24, and 30 months for confirmed vaginal candidiasis are 143, 126, 113, 91, and 52 in the fluconazole group and 132, 108, 90, 72, and 40 in the placebo group, respectively. Kaplan-Meier estimates of the percent of women who remained free of vaginal candidiasis by treatment group.
    Figure 3. Solid line indicates patients receiving weekly fluconazole; dashed line indicates patients receiving placebo. The numbers of patients at risk at 6, 12, 18, 24, and 30 months for confirmed oropharyngeal candidiasis are 138, 119, 105, 87, and 56 for the fluconazole group and 123, 101, 87, 76, and 41 for the placebo group, respectively.
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    Figure 3. Solid line indicates patients receiving weekly fluconazole; dashed line indicates patients receiving placebo. The numbers of patients at risk at 6, 12, 18, 24, and 30 months for confirmed oropharyngeal candidiasis are 138, 119, 105, 87, and 56 for the fluconazole group and 123, 101, 87, 76, and 41 for the placebo group, respectively. Kaplan-Meier estimates of the percentage of women who remained free of oropharyngeal candidiasis by treatment group.

    Among patients who reported a history of mucosal candidiasis at baseline (70% of all patients), 54 patients (32.8 per 100 person-years) receiving fluconazole and 69 patients (58.4 per 100 person-years) receiving placebo had at least one recurrence (RR, 0.51 [CI, 0.35 to 0.75]; P < 0.001), resulting in a difference in risk of 25.6 events per 100 person-years. Among patients who did not report a history of mucosal candidiasis, 18 patients (17.2 per 100 person-years) in the fluconazole group and 24 patients (28.4 per 100 person-years) in the placebo group had at least one episode of candidiasis (RR, 0.69 [CI, 0.35 to 1.34]; P > 0.2), resulting in a difference in risk of 11.2 per 100 person-years.

    As shown by the rates cited above, a history of mucosal candidiasis was a significant predictor of subsequent candidiasis during follow-up. If specific episodes of mucosal candidiasis are considered, the RR for oropharyngeal or esophageal candidiasis associated with a history of oropharyngeal candidiasis was 2.7 (CI, 1.5 to 4.9; P = 0.001) for patients in the placebo group and the RR for vaginal candidiasis associated with two or more episodes of vaginal candidiasis in the year before the start of the study was 3.9 (CI, 1.5 to 9.6; P = 0.004). In patients receiving placebo, other significant predictors of oropharyngeal or esophageal candidiasis were a diagnosis of AIDS (RR, 1.9 [CI, 1.1 to 3.2]; P = 0.03) and use of systemic prophylaxis for P. carinii pneumonia (RR, 2.0 [CI, 1.1 to 3.9]; P = 0.03). Isolation of C. albicans from the vaginal yeast culture at baseline was associated with an increased risk for vaginal candidiasis (RR, 2.7 [CI, 1.1 to 6.8]; P = 0.04).

    Speciation of Vaginal Cultures

    Patients receiving fluconazole were significantly less likely than those receiving placebo to be infected during follow-up (P = 0.018). Of the 969 vaginal cultures obtained at 3-month follow-up visits from patients assigned to receive fluconazole, 319 (33%) yielded fungi, and 340 isolates were recovered. Of the 902 cultures obtained from patients receiving placebo, 371 (41%) yielded fungi; 388 isolates were recovered.

    Candida species that were recovered from vaginal specimens for surveillance varied by treatment group. Longitudinal analysis of specimens that were obtained during follow-up indicated that weekly fluconazole resulted in less isolation of C. albicans than did placebo (relative odds ratio, 0.56 [CI, 0.43 to 0.74]; P < 0.001). For patients receiving fluconazole, C. albicans accounted for 64% of isolates and was found in 53% of patients at least once during follow-up. In women receiving placebo, C. albicans accounted for 79% of isolates and was found in 68% of women at least once.

    In contrast, Candida species other than C. albicans were isolated more often from patients receiving weekly fluconazole than from those receiving placebo (relative odds ratio, 1.24 [CI, 1.01 to 1.53]; P = 0.04). Such species accounted for 33% of isolates and were found at least once during follow-up in 30% of patients receiving fluconazole. Among patients receiving placebo, these species accounted for 19% of isolates and were found in 19% of patients at least once. Candida glabrata was the most commonly isolated species after C. albicans; it was seen in 23% of isolates in the fluconazole group and 14% of isolates in the placebo group. Other species were less common: Candida krusei was found in 1.2% of isolates in the fluconazole group and 1.8% of those in the placebo group, C. tropicalis was found in 2.6% of isolates in the fluconazole group and 1.8% of those in the placebo group, and C. parapsilosis was found in 3.8% of isolates in the fluconazole group and 1.5% of those in the placebo group.

    When vaginal isolates obtained for surveillance or for event documentation from both treatment groups were considered, isolation of C. albicans was more often associated with vaginal candidiasis than was isolation of other Candida organisms. Vaginal candidiasis was confirmed in 18% of 504 cultures in which only C. albicans was isolated, 14% of 35 cultures in which C. albicans and another Candida organism were isolated, and 5% of 191 cultures in which only a Candida species other than C. albicans was isolated.

    Clinical Resistance

    During follow-up, 6 patients receiving fluconazole and 7 patients receiving placebo developed clinical resistance. Twelve of the 13 patients had oropharyngeal or esophageal candidiasis. Candida albicans was isolated from 9 of the 11 cultures that were available. In 10 of the 13 patients with clinical resistance, the CD4+ cell count that immediately preceded the episode of candidiasis was less than 50 cells/mm3; 7 patients had CD4+ cell counts less than 10 cells/mm3.

    In Vitro Resistance

    One hundred seventy-three patients (91 from the fluconazole group and 82 from the placebo group) enrolled in the resistance substudy an average of 10 months after entering the primary study. Patients receiving fluconazole and those receiving placebo who were enrolled in the substudy had similar characteristics. However, these patients had less advanced HIV infection than did those who did not enroll in the substudy: CD4+ cell counts were higher in patients who were in the substudy (215 cells/mm3) than in those who were not (181 cells/mm3; P = 0.02), and the percentage of patients with a history of AIDS was lower in patients who were in the substudy (20%) than in those who were not (31%; P = 0.02).

    Of 83 C. albicans isolates obtained from patients receiving fluconazole, 4 (4.8%) had MICs of 16 µg/mL or greater. Only 4 of 116 isolates (3.4%) obtained from patients receiving placebo reached MICs this high. These resistant isolates of C. albicans were obtained from 4 patients in the fluconazole group and 3 patients in the placebo group (P > 0.2). In both treatment groups, other Candida isolates were more likely than C. albicans to have in vitro resistance to fluconazole. Twenty-nine of 84 Candida isolates other than C. albicans (35%) obtained from patients assigned to fluconazole and 22 of 72 (31%) obtained from patients assigned to placebo had an MIC of 16 µg/mL or greater. These resistant isolates were taken from 16 patients in the fluconazole group and 12 patients in the placebo group (P > 0.2).

    Death and Adverse Events

    One hundred twenty-eight of 323 patients (40%) died; 68 of these patients were from the fluconazole group and 60 were from the placebo group (RR, 1.16 [CI, 0.81 to 1.64]; P > 0.2). Forty-one patients receiving fluconazole and 23 patients receiving placebo had at least one adverse event (RR, 1.30; P > 0.2). No specific toxicities, including hepatotoxicity, were found.

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    Discussion

    We show that a weekly regimen of 200 mg of fluconazole is effective for preventing oropharyngeal and vaginal candidiasis in HIV-infected women: Rates of infection were reduced by approximately one half. Both clinical and in vitro resistance were uncommon, and the incidence of resistance did not differ by treatment group. Women with a history of mucosal candidiasis were at high risk for having an episode during follow-up, and the absolute risk difference for this subgroup was more than twice that for women without a history of candidiasis.

    Other studies have shown that fluconazole is effective for the prevention of recurrent oropharyngeal candidiasis and esophageal candidiasis in HIV-infected patients [21-24], but these trials were smaller, included mostly men, did not evaluate resistance, and (with one exception) used daily administration of fluconazole [23]. Powderly and colleagues [9] studied 407 men and 21 women who had a median CD4+ cell count of about 100 cells/mm3. Fluconazole, 200 mg daily, was associated with a marked reduction in cryptococcal infection and esophageal and oral candidiasis. Despite impressive reductions in risk (of 62% to 83%), the investigators did not recommend routine prophylaxis, citing the low risk for invasive disease, cost, and the risk for azole resistance (this last factor, however, had not been studied) [9].

    Strategies of how best to use azoles in the management of HIV-infected patients are being debated partly because of the lack of data from randomized trials on the prevention and treatment of candidiasis; such data might elucidate the relation between azole use and development of resistance. To our knowledge, our study is the first large long-term randomized study to evaluate azole resistance and the benefit of prophylactic fluconazole. As has been reported by other researchers [25, 26], we found that patients receiving fluconazole were significantly more likely than those receiving placebo to develop vaginal colonization with Candida species other than C. albicans and were less likely to develop vaginal colonization with C. albicans. Most cases of in vitro resistance involved vaginal colonization by Candida species other than C. albicans, but these species were rarely associated with symptomatic vaginal candidiasis. Unlike the results of previous studies, our results showed a low incidence of fluconazole resistance among C. albicans organisms that were isolated from vaginal specimens used for surveillance [25-30].

    These apparently conflicting results about the risk for azole resistance in patients receiving fluconazole may reflect varying exposure to azoles as continuous or intermittent therapy and the less-advanced disease in our patients: Less than one third of our patients had a CD4+ cell count less than 100 cells/mm3 at study entry, and those who were enrolled in the resistance substudy had less advanced disease than those who were not. Resistance seems more likely to occur in isolates obtained from patients who have CD4+ cell counts less than 50 cells/mm3 and substantial previous exposure to fluconazole [11, 29]. Of note are the results of a recently reported observational study that the annual incidence of clinical failure of fluconazole (defined as persistent mucosal candidiasis after 14 days of ≥ 200 mg of fluconazole per day) was 5.8% among 846 HIV-infected persons with a median CD4+ cell count of 14.5 cells/mm3. Candida albicans alone was isolated in 86% of cases [31]. These results are consistent with ours.

    Several limitations of our study should be considered when weighing the clinical implications of our findings. First, the study was not designed to address the influence of weekly fluconazole on the prevention of esophageal candidiasis and invasive fungal disease. The incidence of these events was too low to determine whether weekly fluconazole is an effective prophylaxis. In addition, most episodes of esophageal candidiasis that occurred [30 of 38] were not confirmed; thus, it is possible that some of these episodes represented other manifestations of disease. Second, although oropharyngeal specimens were collected from patients with documented candidiasis, only vaginal specimens were routinely collected for surveillance; this may have caused us to underestimate in vitro resistance. Third, most of our patients had CD4+ cell counts greater than 100 cells/mm3 and therefore may have been at a lower risk for developing resistance, at least early in the course of follow-up. Taken together, these limitations emphasize the need for 1) additional studies that follow cohorts that are well defined in terms of disease stage and azole use to estimate risk for resistance and 2) randomized trials to obtain unbiased estimates of relative risks for resistance that are associated with different regimens for treatment and prophylaxis.

    In summary, weekly fluconazole seems to be a safe and effective strategy for the prevention of oropharyngeal and vaginal candidiasis. Because a history of mucosal candidiasis was an important predictor of recurrent candidiasis and weekly fluconazole was an effective prophylaxis for patients with such a history, we believe that prophylaxis should be considered only for persons who are at a high risk for recurrence and that fluconazole should not be used routinely for primary prophylaxis in all patients.

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    Appendix

    The following are members of the Terry Beirn Community Programs for Clinical Research on AIDS. Addiction Research and Treatment Corporation, Brooklyn, New York: Lawrence S. Brown Jr., MD, MPH, Stanley L John, MD; Harlem AIDS Treatment Group, New York, New York: Cheryl Guity, RN, Judith Sobowale, MD, Fouluke Salu, MD; North Jersey Community Research Initiative, Newark, New Jersey: Nina Regevik, MD, Jean Haspel-Brooks, NP, Victoria Taylor, RN, BS, CCRC; Louisiana Community AIDS Research Program, New Orleans, Louisiana: Suzanne Leblanc, RN, Rebecca Clark, MD, PhD, Jeanne Dumestre, NP; Washington Regional AIDS Program, Washington, D.C.: Brenda Staton, RN, Elizabeth Finley, RN, ANP; Community Consortium, San Francisco, California: Catherine A. Lyons, NP, Carroll C. Child, RN, MSc, Sherrill A. Crawford, RN; Clinical Directors Network of Region II, Inc., New York, New York: Anita Vaughn, MD, Graciela Salvador, MD, Linda Podhurst, PhD; The Research and Education Group, Portland, Oregon: James H. Sampson, MD, Catherine Salveson, MS, MSN; Delaware Community Program for Clinical Research on AIDS, Wilmington, Delaware: William J. Holloway, MD, Lynn Steele Moore, MT, Kathleen M. Furness, MT; Henry Ford Hospital, Detroit, Michigan: Louis D. Saravolatz, MD, Jones Kumi, MD, Norman Markowitz, MD; AIDS Research Consortium of Atlanta, Inc., Atlanta, Georgia: Laura Ray, BS, Kara L. Barrett, RN, Teresa H. Creagh, PhD; Wayne State University, Detroit, Michigan: Lawrence R. Crane, MD, Diana Kinsey-Steele, BSN, RN, Lee Sippel, RN; Denver Community Program for Clinical Research on AIDS, Denver, Colorado: Judith C. Shlay, MD, Jack Rouff, BS, MSW, MBA, Jennifer Saldanha, RN, MA, EdM; Richmond AIDS Consortium, Richmond, Virginia: Evelyn Fisher, MD, Patricia S. Bragg, RN, MPH, Margaret D. Britton, RN, BSN.

    From Wayne State University and Detroit Medical Center, Detroit, Michigan; Harlem Hospital, New York, New York; University of Minnesota, Minneapolis, Minnesota; National Institutes of Health, Bethesda, Maryland; Tulane Medical Center, New Orleans, Louisiana; Newark Community Health Center, Newark, New Jersey; AIDS Research Consortium of Atlanta, Atlanta, Georgia; Addiction Research and Treatment Corporation, Brooklyn, New York; and Medical College of Virginia, Richmond, Virginia.

    Drs. Capps and El-Sadr: Harlem Hospital, 506 Lenox Avenue, New York, NY 10037.

    Ms. Peng: 2221 University Avenue SE, Suite 200, Minneapolis, MN 55414.

    Dr. Goldman: Box 303 UMHC, 420 Delaware Street, University of Minneapolis, Minneapolis, MN 55455.

    Dr. Alston: Solar Building, Room 2B34, 6003 Executive Boulevard, MSC 7640, Bethesda, MD 20892-7640.

    Dr. Besch: Tulane Medical Center, HC28, 1430 Tulane Avenue, New Orleans, LA 70112.

    Dr. Vaughn: 619 Sheridan Avenue, Plainfield, NJ 07060.

    Dr. Thompson: AIDS Research Consortium of Atlanta, 131 Ponce de Leon Avenue SE, Suite 130, Atlanta, GA 30308.

    Dr. Cobb: 213 Copeley Way, North Brunswick, NJ 08902-4575.

    Dr. Kerkering: PO Box 980049, Medical College of Virginia, Richmond, VA 23298-0049.

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