Richard Hafner

Comparison of Amphotericin B with Fluconazole in the Treatment of Acute AIDS-Associated Cryptococcal Meningitis

BACKGROUND Intravenous amphotericin B, with or without flucytosine, is usually standard therapy for cryptococcal meningitis in patients with the acquired immunodeficiency syndrome (AIDS). Fluconazole, an oral triazole agent, represents a promising new approach to the treatment of cryptococcal disease. METHODS In a randomized multicenter trial, we compared intravenous amphotericin B with oral fluconazole as primary therapy for AIDS-associated acute cryptococcal meningitis. Eligible patients, in all of whom the diagnosis had been confirmed by culture, were randomly assigned in a 2:1 ratio to receive either fluconazole (200 mg per day) or amphotericin B. Treatment was considered successful if the patient had had two consecutive negative cerebrospinal fluid cultures by the end of the 10-week treatment period. RESULTS Of the 194 eligible patients, 131 received fluconazole and 63 received amphotericin B (mean daily dose, 0.4 mg per kilogram of body weight in patients with successful treatment and 0.5 mg per kilogram in patients with treatment failure; P = 0.34). Treatment was successful in 25 of the 63 amphotericin B recipients (40 percent; 95 percent confidence interval, 26 percent to 53 percent) and in 44 of the 131 fluconazole recipients (34 percent; 95 percent confidence interval, 25 percent to 42 percent) (P = 0.40). There was no significant difference between the groups in overall mortality due to cryptococcosis (amphotericin vs. fluconazole, 9 of 63 [14 percent] vs. 24 of 131 [18 percent]; P = 0.48); however, mortality during the first two weeks of therapy was higher in the fluconazole group (15 percent vs. 8 percent; P = 0.25). The median length of time to the first negative cerebrospinal fluid culture was 42 days (95 percent confidence interval, 28 to 71) in the amphotericin B group and 64 days (95 percent confidence interval, 53 to 67) in the fluconazole group (P = 0.25). Multivariate analyses identified abnormal mental status (lethargy, somnolence, or obtundation) as the most important predictive factor of a high risk of death during therapy (P less than 0.0001). CONCLUSIONS Fluconazole is an effective alternative to amphotericin B as primary treatment of cryptococcal meningitis in patients with AIDS. Single-drug therapy with either drug is most effective in patients who are at low risk for treatment failure. The optimal therapy for patients at high risk remains to be determined.

Guidelines for preventing opportunistic infections among HIV-infected persons - 2002

Introduction In 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections (OIs) among persons infected with human immunodeficiency virus (HIV) (1-3). These guidelines, which are intended for clinicians and health-care providers and their HIV-infected patients, were revised in 1997 (4) and again in 1999 (5), and have been published in MMWR (1, 4, 5), Clinical Infectious Diseases (2, 6, 7), Annals of Internal Medicine (3, 8), American Family Physician (9, 10), and Pediatrics (11); accompanying editorials have appeared in JAMA (12, 13). Response to these guidelines (e.g., a substantial number of requests for reprints, website contacts, and observations from health-care providers) demonstrates that they have served as a valuable reference for HIV health-care providers. Because the 1995, 1997, and 1999 guidelines included ratings indicating the strength of each recommendation and the quality of supporting evidence, readers have been able to assess the relative importance of each recommendation. Since acquired immunodeficiency syndrome (AIDS) was first recognized 20 years ago, remarkable progress has been made in improving the quality and duration of life for HIV-infected persons in the industrialized world. During the first decade of the epidemic, this improvement occurred because of improved recognition of opportunistic disease processes, improved therapy for acute and chronic complications, and introduction of chemoprophylaxis against key opportunistic pathogens. The second decade of the epidemic has witnessed extraordinary progress in developing highly active antiretroviral therapies (HAART) as well as continuing progress in preventing and treating OIs. HAART has reduced the incidence of OIs and extended life substantially (14-16). HAART is the most effective approach to preventing OIs and should be considered for all HIV-infected persons who qualify for such therapy (14-16). However, certain patients are not ready or able to take HAART, and others have tried HAART regimens but therapy failed. Such patients will benefit from prophylaxis against OIs (15). In addition, prophylaxis against specific OIs continues to provide survival benefits even among persons who are receiving HAART (15). Clearly, since HAART was introduced in the United States in 1995, chemoprophylaxis for OIs need not be lifelong. Antiretroviral therapy can restore immune function. The period of susceptibility to opportunistic processes continues to be accurately indicated by CD4+ T lymphocyte counts for patients who are receiving HAART. Thus, a strategy of stopping primary or secondary prophylaxis for certain patients whose immunity has improved as a consequence of HAART is logical. Stopping prophylactic regimens can simplify treatment, reduce toxicity and drug interactions, lower cost of care, and potentially facilitate adherence to antiretroviral regimens. In 1999, the USPHS/IDSA guidelines reported that stopping primary or secondary prophylaxis for certain pathogens was safe if HAART has led to an increase in CD4+ T lymphocyte counts above specified threshold levels. Recommendations were made for only those pathogens for which adequate clinical data were available. Data generated since 1999 continue to support these recommendations and allow additional recommendations to be made concerning the safety of stopping primary or secondary prophylaxis for other pathogens. For recommendations regarding discontinuing chemoprophylaxis, readers will note that criteria vary by such factors as duration of CD4+ T lymphocyte count increase, and, in the case of secondary prophylaxis, duration of treatment of the initial episode of disease. These differences reflect the criteria used in specific studies. Therefore, certain inconsistencies in the format of these criteria are unavoidable. Although considerable data are now available concerning discontinuing primary and secondary OI prophylaxis, essentially no data are available regarding restarting prophylaxis when the CD4+ T lymphocyte count decreases again to levels at which the patient is likely to again be at risk for OIs. For primary prophylaxis, whether to use the same threshold at which prophylaxis can be stopped (derived from data in studies addressing prophylaxis discontinuation) or to use the threshold below which initial prophylaxis is recommended, is unknown. Therefore, in this revision of the guidelines, in certain cases, ranges are provided for restarting primary or secondary prophylaxis. For prophylaxis against Pneumocystis carinii pneumonia (PCP), the indicated threshold for restarting both primary and secondary prophylaxis is 200 cells/L. For all these recommendations, the Roman numeral ratings reflect the lack of data available to assist in making these decisions (Box). Table. System Used to Rate the Strength of Recommendations and Quality of Supporting Evidence During the development of these revised guidelines, working group members reviewed published manuscripts as well as abstracts and material presented at professional meetings. Periodic teleconferences were held to develop the revisions. Major Changes in These Recommendations Major changes in the guidelines since 1999 include the following: Higher level ratings have been provided for discontinuing primary prophylaxis for PCP and Mycobacterium avium complex (MAC) when CD4+ T lymphocytes have increased to >200 cells/L and >100 cells/L, respectively, for 3 months in response to HAART (AI), and a new recommendation to discontinue primary toxoplasmosis prophylaxis has been provided when the CD4+ T lymphocyte count has increased to >200 cells/L for 3 months (AI). Secondary PCP prophylaxis should be discontinued among patients whose CD4+ T lymphocyte counts have increased to >200 cells/L for 3 months as a consequence of HAART (BII). Secondary prophylaxis for disseminated MAC can be discontinued among patients with a sustained (e.g., 6-month) increase in CD4+ count to >100 cells/L in response to HAART, if they have completed 12 months of MAC therapy and have no symptoms or signs attributable to MAC (CIII). Secondary prophylaxis for toxoplasmosis and cryptococcosis can be discontinued among patients with a sustained increase in CD4+ counts (e.g. 6 months) to >200 cells/L and >100200 cells/L, respectively, in response to HAART, if they have completed their initial therapy and have no symptoms or signs attributable to these pathogens (CIII). The importance of screening all HIV-infected persons for hepatitis C virus (HCV) is emphasized (BIII). Additional information concerning transmission of human herpesvirus 8 infection (HHV-8) is provided. New information regarding drug interactions is provided, chiefly related to rifamycins and antiretroviral drugs. Revised recommendations for vaccinating HIV-infected adults and HIV-exposed or infected children are provided. Using the Information in This Report For each of the 19 diseases covered in this report, specific recommendations are provided that address 1) preventing exposure to opportunistic pathogens, 2) preventing first episodes of disease, and 3) preventing disease recurrences. Recommendations are rated by a revised version of the IDSA rating system (17). In this system, the letters AE signify the strength of the recommendation for or against a preventive measure, and Roman numerals IIII indicate the quality of evidence supporting the recommendation (Box). Because of their length and complexity, tables in this report are grouped together and follow the references. Tables appear in the following order: Table 1 Dosages for prophylaxis to prevent first episode of opportunistic disease among infected adults and adolescents; Table 1. Prophylaxis to Prevent First Episode of Opportunistic Disease among Adults and Adolescents Infected with Human Immunodeficiency Virus (HIV) Table 2 Dosages for prophylaxis to prevent recurrence of opportunistic disease among HIV-infected adults and adolescents; Table 2. Prophylaxis to Prevent Recurrence of Opportunistic Disease, after Chemotherapy for Acute Disease, among Adults and Adolescents Infected with Human Immunodeficiency Virus (HIV) Table 3 Effects of food on drugs used to treat OIs; Table 3. Effects of Food on Drugs Used to Prevent Opportunistic Infections Table 4 Effects of medications on drugs used to treat OIs; Table 4. Effects of Medications on Drugs Used to Prevent Opportunistic Infections Table 5 Effects of OI medications on drugs commonly administered to HIV-infected persons; Table 5. Effects of Opportunistic Infection Medications on Antiretroviral Drugs Commonly Administered to Persons Infected with Human Immunodeficiency Virus (HIV) Table 6 Adverse effects of drugs used to prevent OIs; Table 6. Adverse Effects of Drugs Used in Preventing Opportunistic Infections Table 7 Dosages of drugs for preventing OIs for persons with renal insufficiency; Table 7. Dosing of Drugs for Primary Prevention of or Maintenance Therapy for Opportunistic Infections Related to Renal Insufficiency Table 8 Costs of agents recommended for preventing OIs among adults with HIV infection; Table 8. Wholesale Acquisition Costs of Agents Recommended for Preventing Opportunistic Infections among Adults Infected with Human Immunodeficiency Virus Table 9 Immunologic categories for HIV-infected children; Table 9. Immunologic Categories for Human Immunodeficiency Virus-Infected Children, Based on Age-Specific CD4+ T Lymphocyte Counts and Percentage of Total Lymphocytes Table 10 Immunization schedule for HIV-infected children; Table 10. Recommended Immunization Schedule for Human Immunodeficiency Virus (HIV)-Infected Children Table 11 Dosages for prophylaxis to prevent first episode of opportunistic disease among HIV-infected infants and children; Table 11. Prophylaxis to Prevent First Episode of Opportunistic Disease among Infants and Children Infected with Human Immunodeficiency Virus Tabl

Toxoplasmic Encephalitis in Patients with the Acquired Immunodeficiency Syndrome

BACKGROUND In patients with the acquired immunodeficiency syndrome (AIDS), toxoplasmic encephalitis is usually a presumptive diagnosis based on the clinical manifestations, a positive antitoxoplasma-antibody titer, and characteristic neuroradiologic abnormalities. A response to specific therapy helps to confirm the diagnosis, but it is unclear how rapid the response should be. We studied the course of patients treated for acute toxoplasmic encephalitis and evaluated objective clinical criteria for this empirical diagnosis. METHODS A quantifiable neurologic assessment was used prospectively to evaluate the clinical outcome of patients with AIDS and toxoplasmic encephalitis who were treated with oral clindamycin (600 mg four times a day) and pyrimethamine (75 mg every day) for six weeks. RESULTS Thirty-five of 49 patients (71 percent) responded to therapy, and 30 of these (86 percent) had improvement by day 7. Thirty-two of those with a response (91 percent) improved with respect to at least half of their base-line abnormalities by day 14. Improvement in neurologic abnormalities within 7 to 14 days after the start of therapy was strongly associated with the neurologic response at 6 weeks. The four patients in whom treatment failed and the two patients with lymphoma had progressing neurologic abnormalities or new abnormalities during the first 12 days of therapy. Nonlocalizing abnormalities (headache and seizure) improved regardless of the clinical outcome. CONCLUSIONS Oral clindamycin and pyrimethamine are an effective treatment for toxoplasmic encephalitis. Patients who have early neurologic deterioration despite treatment or who do not improve neurologically after 10 to 14 days of appropriate antitoxoplasma therapy should be considered candidates for brain biopsy.

A Controlled Trial Comparing Foscarnet with Vidarabine for Acyclovir-Resistant Mucocutaneous Herpes Simplex in the Acquired Immunodeficiency Syndrome

BACKGROUND AND METHODS Most strains of herpes simplex virus that are resistant to acyclovir are susceptible in vitro to both foscarnet and vidarabine. We conducted a randomized trial to compare foscarnet with vidarabine in 14 patients with the acquired immunodeficiency syndrome (AIDS) and mucocutaneous herpetic lesions that had been unresponsive to intravenous therapy with acyclovir for a minimum of 10 days. The patients were randomly assigned to receive either foscarnet (40 mg per kilogram of body weight intravenously every 8 hours) or vidarabine (15 mg per kilogram per day intravenously) for 10 to 42 days. In the isolates of herpes simplex virus we documented in vitro resistance to acyclovir and susceptibility to foscarnet and vidarabine. RESULTS The lesions in all eight patients assigned to foscarnet healed completely after 10 to 24 days of therapy. In contrast, vidarabine was discontinued because of failure in all six patients assigned to receive it. The time to complete healing (P = 0.01), time to 50 percent reductions in the size of the lesions (P = 0.01) and the pain score (P = 0.004), and time to the end of viral shedding (P = 0.006) were all significantly shorter in the patients assigned to foscarnet. Three patients had new neurologic abnormalities while receiving vidarabine. No patient discontinued foscarnet because of toxicity. Although initial recurrences of herpes simplex infection after the index lesion had healed tended to be susceptible to acyclovir, acyclovir-resistant infection eventually recurred in every healed patient, a median of 42.5 days (range, 14 to 191) after foscarnet was discontinued. CONCLUSIONS For the treatment of acyclovir-resistant herpes simplex infection in patients with AIDS, foscarnet has superior efficacy and less frequent serious toxicity than vidarabine. Once the treatment is stopped, however; there is a high frequency of relapse.

A Controlled Trial of Fluconazole or Amphotericin B to Prevent Relapse of Cryptococcal Meningitis in Patients with the Acquired Immunodeficiency Syndrome

BACKGROUND After primary treatment for cryptococcal meningitis, patients with the acquired immunodeficiency syndrome (AIDS) require some form of continued suppressive therapy to prevent relapse. METHODS We conducted a multicenter, randomized trial that compared fluconazole (200 mg per day given orally) with amphotericin B (1 mg per kilogram of body weight per week given intravenously) in patients with AIDS who had completed primary therapy for cryptococcal meningitis with amphotericin B (greater than or equal to 15 mg per kilogram). To be eligible, patients had to have at least two negative cultures of cerebrospinal fluid immediately before randomization. The primary end point was relapse of cryptococcal disease as confirmed by biopsy or culture. RESULTS Of 218 patients initially enrolled, 119 were assigned to fluconazole and 99 to amphotericin B. Twenty-three patients were found not to have met the entry criteria; six other patients assigned to amphotericin B did not receive it and were lost to follow-up. Of the remaining 189 patients, after a median follow-up of 286 days 14 of 78 receiving amphotericin B (18 percent) and 2 of 111 assigned to fluconazole (2 percent) had relapses of symptomatic cryptococcal disease (P less than 0.001 by Fishers exact test). There was a difference of 19 percent in the estimated probability of remaining relapse-free at one year between the fluconazole group (97 percent) and the amphotericin B group (78 percent) (95 percent confidence interval, 7 percent to 31 percent; P less than 0.001). Serious drug-related toxicity was more frequent in the amphotericin B group (P = 0.02), as were bacterial infections (P = 0.004) and bacteremia (P = 0.002). CONCLUSIONS Fluconazole taken by mouth is superior to weekly intravenous therapy with amphotericin B to prevent relapse in patients with AIDS-associated cryptococcal meningitis after primary treatment with amphotericin B.

Variation of Chest Radiographic Patterns in Pulmonary Tuberculosis by Degree of Human Immunodeficiency Virus-Related Immunosuppression

Our aim was to evaluate the effect of human immunodeficiency virus (HIV) disease stage on chest radiographic (CXR) findings among patients with HIV-related pulmonary tuberculosis (TB). Data are from a prospective multicenter treatment trial for HIV-related TB. Baseline CXR findings and CD4+ lymphocyte counts were compared among patients with HIV-related TB. Data from published studies describing CXR findings in HIV-infected patients were reviewed and a pooled-data analysis was conducted. Of 135 patients with culture-confirmed HIV-related TB, 128 had both CXR and CD4+ lymphocyte data. CD4+ lymphocyte counts of < 200/mm3 (n = 98) were significantly associated with hilar/mediastinal adenopathy on CXR (30%, vs. 7% with counts > or = 200/mm3; P = .01); counts of > or = 200/mm3 (n = 30) more frequently were associated with cavitation (20% vs. 7%; P = .08). Analyses of these results, pooled with other published data, confirmed these findings. This study demonstrates associations of certain CXR findings with HIV disease stage. Knowledge of the degree of immunosuppression is important when evaluating CXR findings in HIV-infected patients.

A Comparison of Itraconazole Versus Fluconazole as Maintenance Therapy for AIDS-Associated Cryptococcal Meningitis

This study was designed to compare the effectiveness of fluconazole vs. itraconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. HIV-infected patients who had been successfully treated (achieved negative culture of CSF) for a first episode of cryptococcal meningitis were randomized to receive fluconazole or itraconazole, both at 200 mg/d, for 12 months. The study was stopped prematurely on the recommendation of an independent Data Safety and Monitoring Board. At the time, 13 (23%) of 57 itraconazole recipients had experienced culture-positive relapse, compared with 2 relapses (4%) noted among 51 fluconazole recipients (P = .006). The factor best associated with relapse was the patient having not received flucytosine during the initial 2 weeks of primary treatment for cryptococcal disease (relative risk = 5.88; 95% confidence interval, 1.27-27.14; P = .04). Fluconazole remains the treatment of choice for maintenance therapy for AIDS-associated cryptococcal disease. Flucytosine may contribute to the prevention of relapse if used during the first 2 weeks of primary therapy.

Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome

PURPOSE Amphotericin B has been the treatment of choice for disseminated histoplasmosis in patients with acquired immunodeficiency syndrome (AIDS). Oral antifungal agents would be welcome alternatives to standard treatment of disseminated histoplasmosis in less severe cases. The purpose of this study was to assess the efficacy and safety of itraconazole therapy in patients with AIDS and disseminated histoplasmosis. PATIENTS AND METHODS This was a multicenter, open-label, nonrandomized prospective trial conducted in university hospitals of the AIDS Clinical Trial Group. All patients had AIDS and first episodes of disseminated histoplasmosis. Patients with central nervous system involvement or with severe clinical manifestations were excluded. Patients were treated with itraconazole BID by mouth 300 mg for 3 days and then 200 mg BID for 12 weeks. Resolution of clinical findings, clearance of positive cultures, and drug tolerance were the main outcome measurements. A secondary objective was effect of therapy on Histoplasma capsulatum var capsulatum antigen levels. RESULTS Of 59 evaluable patients, 50 (85%) responded to therapy. Five patients withdrew because of progressive infection, 1 died of a presumed pulmonary embolus within the first week of therapy without improvement, 2 withdrew because of toxicity, and 1 was lost to follow-up after week 2 of therapy. Patients with moderately severe clinical (fever > 39.5 degrees C or Karnofsky score < 60) or laboratory abnormalities (alkaline phosphatase > 5 times normal or albumin < 3 g/dL) at baseline tended to respond more poorly than did other patients. Resolution of complaints of fever and improvement in fatigue occurred after a median of 3 and 6 weeks, respectively, and weight gain after 2 weeks. Fungemia cleared after a median of 1 week. H capsulatum var capsulatum antigen cleared from the urine and serum at rates of 0.2 and 0.3 units per week, respectively. CONCLUSIONS Itraconazole is safe and effective induction therapy for mild disseminated histoplasmosis in patients with AIDS, offering an alternative to amphotericin B in such cases. Patients with moderately severe or severe histoplasmosis should first be treated with amphotericin B and then may be switched to itraconazole after achieving clinical improvement.

Drug-resistant tuberculosis: time for visionary political leadership

Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates roughly 630 000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis. Increased population movement, the continuing HIV pandemic, and the rise in MDR tuberculosis pose formidable challenges to the global control of tuberculosis. We provide an overview of the global burden of drug-resistant disease; discuss the social, health service, management, and control issues that fuel and sustain the epidemic; and suggest specific recommendations for important next steps. Visionary political leadership is needed to curb the rise of MDR and XDR tuberculosis worldwide, through sustained funding and the implementation of global and regional action plans.

Prevention of Relapse of Histoplasmosis with Itraconazole in Patients with the Acquired Immunodeficiency Syndrome

Amphotericin B is commonly used to treat histoplasmosis in patients with the acquired immunodeficiency syndrome (AIDS). In uncontrolled studies, this drug was highly effective for initial or induction treatment of disseminated histoplasmosis in patients with AIDS [1]. However, the occurrence of relapse within 6 to 18 months necessitated continued maintenance treatment to suppress persistent infection [1]. As many as 50% of patients relapsed while receiving maintenance therapy with ketoconazole, 200 to 400 mg daily [1]. Relapse occurs in as many as 20% of patients who receive 50 to 100 mg of amphotericin B weekly or biweekly as maintenance therapy [1, 2]. The need for intravenous access, the occurrence of catheter-related complications, the inconvenience of intravenous infusion, the gastrointestinal and systemic toxicity, the requirement for laboratory monitoring, and the expense of home intravenous treatment further limit the use of amphotericin B as maintenance therapy in patients who have had histoplasmosis. Itraconazole and fluconazole offer advantages over amphotericin B or ketoconazole as maintenance therapy for fungal disease in patients with AIDS [3]. Both are well absorbed after oral administration and cause few side effects. Although both drugs have been effective in the treatment of murine [4, 5] and human histoplasmosis [6], itraconazole was selected for further study because there is more experience with it in the treatment of histoplasmosis in humans [6]. We carried out an open-label, nonrandomized trial to assess the efficacy and tolerance of itraconazole in the prevention of histoplasmosis relapse in patients with AIDS who had been treated with amphotericin B. Methods Patients Participants were at least 13 years old, had human immunodeficiency virus (HIV) infection, and had received amphotericin B induction therapy at a total dose of at least 15 mg/kg body weight administered for 3 to 12 weeks for proven disseminated histoplasmosis within 6 weeks before enrollment. Successful induction treatment was documented by the absence of clinical findings associated with histoplasmosis and negative fungal blood cultures at the time of enrollment. Patients were excluded from the study if they had a history of allergy to azole antifungal agents; a bilirubin level more than 2.5 times the upper limit of normal; an alanine aminotransferase level more than five times the upper limit of normal; an alkaline phosphatase level more than five times the upper limit of normal; a creatinine level more than three times the upper limit of normal; neutropenia (neutrophil count, <0.75 109/L) or thrombocytopenia (platelet count, <75 109); a Karnofsky score of less than 60; and concurrent treatment with phenytoin, barbiturates, rifampin, corticosteroids in doses exceeding those used in maintenance therapy for adrenal insufficiency, cytotoxic chemotherapy, systemic antifungal agents, or investigational drugs. Patients requiring histamine blockers or antacids were not allowed to receive such therapy within 4 hours of itraconazole administration. Intervention and Evaluation Eligible patients received itraconazole, 200 mg twice daily orally with meals. Patients were evaluated for efficacy and toxicity until the last enrolled patient completed at least 52 weeks of treatment. Patients were evaluated biweekly for 4 weeks, monthly for 12 months, and then bimonthly until the completion of the study. Each evaluation included an assessment of clinical findings to identify evidence of histoplasmosis relapse or side effects of itraconazole therapy, complete blood counts, serum chemistries, and determinations of Histoplasma capsulatum variety capsulatum antigen levels in urine and serum. Plasma itraconazole levels were measured at weeks 2, 4, 12, 24, and 36, and blood was collected for fungal culture at enrollment and at weeks 12, 24, 36, and 52, or as indicated based on clinical findings. Adverse events were graded using the standard AIDS Clinical Trial Group severity scoring system. Selected laboratory criteria are listed in the results section, but complete criteria are available on request. Plasma itraconazole concentrations were measured by bioassay at the Fungus Testing Laboratory, San Antonio, Texas [7]. Histoplasma capsulatum var. capsulatum antigen levels in urine and serum were measured at Indiana University [8, 9]. Antigen levels were measured as specimens were received and in batch after all patients had completed 1 year of treatment or had withdrawn from the study for other reasons. All specimens were stored at 70C. Statistical Analysis The distribution of the times to events was estimated using the method of Kaplan and Meier [10]. In the determinations of duration of follow-up, patients who died were not considered to be lost to follow-up. Mean antigen levels at initiation and completion of 52 weeks of study therapy were compared using a paired t-test. Differences in proportions of patients with positive antigen results at initiation and completion of 52 weeks of study therapy were compared using the McNemar test. Results Forty-two patients were enrolled in the study from 10 AIDS Clinical Trials units and 2 Mycoses Study Group sites. Forty-one of the 42 patients were diagnosed with disseminated histoplasmosis based on demonstration of organisms consistent with H. capsulatum var. capsulatum in extrapulmonary tissues by special stain or culture; the diagnosis in the remaining patient was based on detection of H. capsulatum var. capsulatum antigen in urine and demonstration of granulomas in the bone marrow. Baseline demographic, clinical, and laboratory characteristics, as well as data on induction antifungal therapy, are summarized in Table 1. The median CD4 lymphocyte count at baseline for these patients was 0.047 109/L (range, 0.005 to 0.272). The CD4 count was less than 0.050 109/L in 19 of 37 patients (51%), less than 0.100 109/L in 30 patients (81%), and less than 0.200 109/L in 36 patients (97%); CD4 counts were not available in 5 patients. Disseminated histoplasmosis was the primary AIDS-defining illness in 25 patients (60%). Disseminated histoplasmosis occurred a median of 3 months (range, 0.3 to 12.8 months) after the AIDS-defining illness in the 17 patients in whom histoplasmosis was a second or later AIDS-defining event. Thirty-eight patients had received amphotericin B at a total dose of at least 15 mg/kg given over 4 to 12 weeks, and the remaining 4 patients had received a total dose of at least 10 mg/kg. The median total dosage was 20.9 mg/kg (range, 14.0 to 59.2 mg/kg) given over a median of 36 days (range, 9 to 132 days). Table 1. Baseline Characteristics of 42 Patients at Enrollment Of the 42 patients who enrolled in the study, 15 failed to meet all eligibility criteria but were included in the data analysis. Reasons for failure to meet eligibility criteria included a neutrophil count of less than 0.75 109/L or a platelet count of less than 75 109/L (five patients), induction treatment with less than 15 mg/kg of amphotericin B (four patients), completion of induction therapy more than 6 weeks before enrollment (three patients), and negative cultures at the time of diagnosis of histoplasmosis (three patients). In two of these latter three patients, silver staining of lymph node specimens showed organisms resembling H. capsulatum var. capsulatum; in the third, antigen was detected in the urine. Compliance Compliance with itraconazole treatment was assessed by counts of returned medication and measurement of plasma itraconazole concentrations at specified visits. Less than 25% of medication was returned at 692 of the 720 visits (96%). The 28 visits at which more than 25% of medication was returned were made by 16 patients (38%). Plasma itraconazole concentrations of at least 0.75 g/mL were documented for 233 of 255 determinations (91%) in the 40 patients for whom results were available. Overall, 25 of the 40 patients (63%) had concentrations of at least 0.75 g/mL for every determination. In the remaining 15 patients (37%), concentrations were less than 0.75 g/mL for 31 of 95 determinations (33%). Itraconazole concentrations were determined in specimens obtained at (four occasions) or within 4 weeks (nine occasions) of the visits for which more than 25% of unused medication was returned. Concentrations were at least 0.75 g/mL in 10 of the 13 specimens (77%). Follow-Up The median duration of follow-up was 109 weeks (range, 4 to 134 weeks), and the median survival time was 98 weeks (range, 4 to 134+ weeks) (Figure 1). As of 4 February 1992, when the data were analyzed, 17 patients continued to receive study treatment. Among the 25 patients who were no longer receiving therapy, reasons for discontinuation included death (15 patients), voluntary withdrawal (3 patients), inability to keep scheduled follow-up (3 patients), preterminal HIV-associated disease (2 patients who died within 7 days of discontinuing treatment), toxicity (1 patient), and relapse (1 patient) (Table 2). Of the 10 patients who withdrew or were withdrawn from study, 6 subsequently died. Figure 1. Kaplan-Meier estimates of survival and relapse. Overall, 21 patients had died as of 4 February 1992. Causes of death included progressive HIV infection with wasting (10 patients), opportunistic infections (9 patients), and HIV-related malignancy (2 patients). Of the 9 patients with opportunistic infections, 2 had disseminated Mycobacterium avium-intracellulare complex infection, 2 had pneumonia of uncertain cause, and 1 each had toxoplasmosis, sepsis, disseminated Pneumocystis carinii infection, an undiagnosed central nervous system syndrome with paralysis and coma, and disseminated histoplasmosis. Only 1 patient had an autopsy, and disseminated Pneumocystis carinii infection was found to be the cause of death; cultures for H. capsulatum var. capsulatum were negative. Risk for Relapse One proven and one possible relapse occurred during the study. The prove