A controlled trial of itraconazole as primary prophylaxis for systemic fungal infections in patients with advanced human immunodeficiency virus infection in Thailand. A multicentre, randomized, double-blind, placebo-controlled trial of primary cryptococcal meningitis prophylaxis in HIV-infected patients with severe immune deficiency. A randomized, double-blind, placebo-controlled study of itraconazole capsules for the prevention of deep fungal infections in immunodeficient patients with HIV infection. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomized, placebo-controlled, double-blind study. National Institute of Allergy and Infectious Diseases Mycoses Study Group. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Antifungal prophylaxis during remission induction therapy for acute leukemia fluconazole versus intravenous amphotericin B. A dose comparison study of a new triazole antifungal (D0870) in HIV-positive patients with oral candidiasis. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group.
Cryptococcal meningitis and Penicillium marneffei infection are common serious fungal infections in patients infected with human immunodeficiency virus (HIV) in Southeast Asia. In a prospective, double-blind trial, 63 patients with HIV infection and CD4+ lymphocyte counts of <200 cells/microL were randomized to receive oral itraconazole (200 mg per day), and 66 similar patients received a matched placebo. Both groups were monitored for evidence of invasive fungal infections. Baseline characteristics and the CD4+ cell counts of the 2 groups were similar. In the intent-to-treat analysis, a systemic fungal infection developed in 1 patient (1.6%) assigned to receive itraconazole (P. marneffei) and in 11 patients (16.7%) given placebo (7 patients had cryptococcal meningitis, and 4 patients had P. marneffei infection; P=.003, by the log-rank test). The incidence of recurrent or refractory mucosal candidiasis was significantly reduced in the itraconazole group. The 2 groups did not differ with regard to adverse effects. Primary prophylaxis with oral itraconazole is well tolerated and prevents cryptococcosis and penicilliosis marneffei in patients with advanced HIV infection, especially those with CD4+ lymphocyte counts of <100 cells/microL. However, prophylaxis with itraconazole was not found to be associated with a survival advantage when it was given to patients with advanced HIV disease. To assess the efficacy and survival benefit of low-dose fluconazole (400 mg weekly) for primary prophylaxis for cryptococcal meningitis in patients with advanced HIV infection.
                A prospective multicentre, randomized, double-blind, placebo-controlled study was carried out in HIV-infected patients with CD4 counts <100 cells/microL.
                Of 90 patients enrolled, 44 received fluconazole and 46 received placebo. The baseline characteristics were similar in the two groups. On an intent-to-treat basis, 10 cases of cryptococcal meningitis developed, three (6.8%) in the fluconazole group and seven (15.2%) in the placebo group. Patients in the placebo group were more likely to develop cryptococcal meningitis than those in the fluconazole group [hazard ratio=2.23; 95% confidence interval (CI): 0.58-8.63; P=0.245]. The survival benefit of fluconazole was greater than that of the placebo. The number of deaths per 10 000 person-days was 2.7 for the fluconazole group (2/7342) and 11.7 for the placebo group (9/7713) (rate difference=9; 95% CI: 0.4-17.5; P=0.046). Based on survival analysis, patients in the placebo group were 4.3 times more likely to die than those in the fluconazole group (95% CI: 0.9-19.8; P=0.065).
                Fluconazole 400 mg once weekly for primary prophylaxis for cryptococcal meningitis in Thailand should be considered in HIV-infected patients, as our study suggested a survival benefit. However, a larger study should be conducted to confirm our findings. To determine whether systemic or deep fungal infections can be prevented, a double-blind, placebo-controlled, phase III trial of itraconazole prophylaxis was undertaken in HIV-infected patients.
                HIV-1 infected patients with CD4 counts < 300 cells/microL were treated with itraconazole (200 mg per day) or matching placebo and followed for 2 years. Development of deep fungal infections, episodes of mucocutaneous candidiasis, change in CD4 count, survival and safety data were collected at each study visit.
                Three hundred and seventy-four patients received study medication, 187 were given itraconazole and 187 matching placebo. Time to development of deep fungal infection did not differ between groups, in an intention to treat analysis. Low CD4 cell count and prior use of Pneumocystis carinii pneumonia (PCP) prophylaxis were significantly associated with a more rapid development of deep fungal infection (P = 0.044 and 0.017, respectively). Itraconazole treatment significantly reduced the incidence of oral candidosis (25% vs. 48% P < 0.001) and time to development of oral candidosis (508 vs. 413 days, P < 0.001) but not the number of deep fungal infections (11 vs. 13). Survival did not differ significantly between groups (nine vs. 14 deaths). CD4 counts decreased significantly over time in both study arms. Adverse events did not differ between groups; 20% vs. 23% stopped study medication due to an adverse experience.
                Although itraconazole prophylaxis significantly reduced the number and time to development of oral candidosis, too few episodes of deep fungal infection were noted to determine whether itraconazole prophylaxis was effective for this condition. Chronic itraconazole treatment is well tolerated in HIV-infected patients with marked immunodeficiency. In a prospective, randomized, double-blind trial, 149 patients with advanced human immunodeficiency virus (HIV) infection were randomized to receive itraconazole capsules (200 mg daily) and 146 to receive a matched placebo. Both groups were monitored for evidence of fungal infections. Baseline characteristics of the two groups were similar. Failure of prophylaxis occurred in 29 (19%) of the itraconazole recipients and 42 (29%) of the placebo recipients (P = .004; log-rank test). There were 6 invasive fungal infections in the itraconazole group (4, histoplasmosis; 1, cryptococcosis; 1, aspergillosis) and 19 in the placebo group (10, histoplasmosis; 8, cryptococcosis; 1, aspergillosis) (P = .0007; log-rank test). Itraconazole significantly delayed time to onset of histoplasmosis (P = .03; log-rank test) and cryptococcosis (P = .0005; log-rank test). Prophylaxis failure due to recurrent or refractory mucosal candidiasis occurred with similar frequency in the two groups (itraconazole, 15%; placebo, 16%). A survival benefit was not demonstrated. Itraconazole generally was well tolerated. Primary prophylaxis with itraconazole capsules prevents histoplasmosis and cryptococcosis in patients with HIV infection. Cryptococcal meningitis and other serious fungal infections are common complications in patients infected with the human immunodeficiency virus (HIV). Fluconazole is effective for long-term suppression of many fungal infections, but its effectiveness as primary prophylaxis had not been adequately evaluated.
                We conducted a prospective, randomized trial that compared fluconazole (200 mg per day) with clotrimazole troches (10 mg taken five times daily) in patients who were also participating in a randomized trial of primary prophylaxis for Pneumocystis carinii pneumonia.
                After a median follow-up of 35 months, invasive fungal infections had developed in 4.1 percent of the patients in the fluconazole group (9 of 217) and in 10.9 percent of those in the clotrimazole group (23 of 211; relative hazard, as adjusted for the CD4+ count, 3.3; 95 percent confidence interval, 1.5 to 7.6). Of the 32 invasive fungal infections, 17 were cryptococcosis (2 in the fluconazole group and 15 in the clotrimazole group; adjusted relative hazard, 8.5; 95 percent confidence interval, 1.9 to 37.6). The benefit of fluconazole was greater for the patients with 50 or fewer CD4+ cells per cubic millimeter than for the patients with higher counts. Fluconazole was also effective in preventing esophageal candidiasis (adjusted relative hazard, 5.8; 95 percent confidence interval, 1.7 to 20.0; P = 0.004) and confirmed and presumed oropharyngeal candidiasis (5.7 and 38.1 cases per 100 years of follow-up in the fluconazole and clotrimazole groups, respectively; P < 0.001). Survival was similar in the two groups.
                Fluconazole taken prophylactically reduces the frequency of cryptococcosis, esophageal candidiasis, and superficial fungal infections in HIV-infected patients, especially those with 50 or fewer CD4+ lymphocytes per cubic millimeter, but the drug does not reduce overall mortality. It frequently takes more than 2 weeks for drug treatments for cryptococcal meningitis to sterilise cerebrospinal fluid (CSF). In-vitro and animal studies lend support to the use of combinations of amphotericin B, flucytosine, and fluconazole for treatment of cryptococcosis. We compared the fungicidal activity of combinations of these drugs for initial treatment of patients with cryptococcal meningitis.
                64 patients with a first episode of HIV-associated cryptococcal meningitis were randomised to initial treatment with: amphotericin B (0.7 mg/kg daily); amphotericin B plus flucytosine (100 mg/kg daily); amphotericin B plus fluconazole (400 mg daily); or triple therapy with amphotericin B, flucytosine, and fluconazole. Our primary endpoint was fungicidal activity, measured by the rate of reduction in CSF cryptococcal colony-forming units (CFU) from serial quantitative CSF cultures on days 3, 7, and 14 of treatment.
                Baseline CSF CFU counts were an important prognostic factor. Clearance of cryptococci from the CSF was exponential and was significantly faster with amphotericin B plus flucytosine than with amphotericin B alone (p=0.0006), amphotericin B plus fluconazole ( p=0.02), or triple therapy (p=0.02).
                At these doses, amphotericin B plus flucytosine is the most rapidly fungicidal regimen. Quantification of CSF cultures provides a powerful new means to accurately assess the fungicidal activity of new treatment regimens for cryptococcal meningitis. Fungal infection is a frequent and often fatal complication in patients undergoing remission induction therapy for acute leukemia. Although candidiasis is the most common infection, mold infections are increasing in frequency. Fluconazole (FLU) is a new antifungal agent that has been used successfully to treat Candida infections and has modest activity against aspergillosis in animal models. Subtherapeutic doses of amphotericin B (AMB) have been considered effective as prophylaxis in these patients. This study was designed to compare the efficacy and toxicity of these agents as antifungal prophylaxis.
                Adults with acute leukemia undergoing remission induction chemotherapy randomly were assigned to receive antifungal prophylaxis with AMB (0.5 mg/kg three times weekly) or FLU (400 mg daily). Trimethoprim-sulfamethoxazole was administered as an antibacterial prophylaxis. Prophylaxis was continued until the patient achieved complete remission or was treated for 8 weeks without antileukemic response. Prophylaxis was discontinued if the patient experienced a possible or proven fungal infection or a serious toxicity.
                Overall, 58% of the 36 patients assigned to AMB successfully completed prophylaxis compared with 80% of the 41 patients assigned to FLU (< 0.05). Proven, probable, or possible fungal infections occurred in 31% and 17% of the patients, respectively. The risk of discontinuing prophylaxis due to fungal infection or toxicity increased with time in the study and was significantly greater for AMB (P = 0.02).
                At the dose used in this study, AMB was no more effective and was more toxic than FLU for prophylaxis of fungal infections in patients undergoing remission induction chemotherapy for acute leukemia. This multicentre study evaluated the clinical efficacy and tolerability of D0870 in treating oropharyngeal candidiasis in HIV-positive patients who had no history of clinical resistance to fluconazole.
                Three regimens were evaluated in two phases. In phase I a 50 mg initial dose was followed by 10 mg for 4 days (Group 1). In phase II a 100 mg initial dose was followed by 25 mg for 4 days (Group 2), or 10 mg for 5 days (Group 3).
                Clinical cure was obtained in 27 patients of a total of 35 (77%) and six other patients improved (17%). Two patients at the lowest dose failed and both had very low plasma concentration of D0870. No association was found between clinical outcome; minimum inhibitory concentration of D0870 pre-therapy for Candida albicans, maximum recorded plasma D0870 concentration, cfu of culture or CD4 cell count at entry. Overall, 37% of the patients experienced relapse during the 2 weeks post therapy. Tolerance was excellent. Mild adverse events possibly related to the study drug were recorded in five patients.
                D0870 demonstrates excellent efficacy at low doses in the treatment of HIV-related OPC and exhibits a favourable safety profile. Treatment with low-dose amphotericin B (0.4 mg per kilogram of body weight per day) or oral azole therapy in patients with the acquired immunodeficiency syndrome (AIDS) and cryptococcal meningitis has been associated with high mortality and low rates of cerebrospinal fluid sterilization.
                In a double-blind multicenter trial we randomly assigned patients with a first episode of AIDS-associated cryptococcal meningitis to treatment with higher-dose amphotericin B (0.7 mg per kilogram per day) with or without flucytosine (100 mg per kilogram per day) for two weeks (step one), followed by eight weeks of treatment with itraconazole (400 mg per day) or fluconazole (400 mg per day) (step two). Treatment was considered successful if cerebrospinal fluid cultures were negative at 2 and 10 weeks or if the patient was clinically stable at 2 weeks and asymptomatic at 10 weeks.
                At two weeks, the cerebrospinal fluid cultures were negative in 60 percent of the 202 patients receiving amphotericin B plus flucytosine and in 51 percent of the 179 receiving amphotericin B alone (P=0.06). Elevated intracranial pressure was associated with death in 13 of 14 patients during step one. The clinical outcome did not differ significantly between the two groups. Seventy-two percent of the 151 fluconazole recipients and 60 percent of the 155 itraconazole recipients had negative cultures at 10 weeks (95 percent confidence interval for the difference in percentages, -100 to 21). The proportion of patients who had clinical responses was similar with fluconazole (68 percent) and itraconazole (70 percent). Overall mortality was 5.5 percent in the first two weeks and 3.9 percent in the next eight weeks, with no significant difference between the groups. In a multivariate analysis, the addition of flucytosine during the initial two weeks and treatment with fluconazole for the next eight weeks were independently associated with cerebrospinal fluid sterilization.
                For the initial treatment of AIDS-associated cryptococcal meningitis, the use of higher-dose amphotericin B plus flucytosine is associated with an increased rate of cerebrospinal fluid sterilization and decreased mortality at two weeks, as compared with regimens used in previous studies. Although consolidation therapy with fluconazole is associated with a higher rate of cerebrospinal fluid sterilization, itraconazole may be a suitable alternative for patients unable to take fluconazole.
Antifungal primary prophylaxis with either itraconazole or fluconazole is effective in reducing the incidence of cryptococcal disease in adults with advanced HIV disease. However, neither of these interventions has a clear effect on overall mortality. Further research is needed to better understand these interventions and the populations in which they may be most effective.