Peter T. Frame

Bone Marrow Toxicity Associated with 5-Fluorocytosine Therapy

Bone marrow toxicity occurred in 4 of 15 patients treated with 5-fluorocytosine (5-FC) for serious fungal infections. The development of marrow toxicity appeared to be related to serum 5-FC levels of 125 μg/ml or greater. In three patients, accumulation of toxic levels of 5-FC was related to diminished renal function. One patient with acute renal failure and prolonged high levels of 5-FC developed marrow aplasia and died of bacterial sepsis. Three patients experienced leukopenia, which was readily reversed when the dosage of 5-FC was decreased and the serum concentration was lowered. With careful monitoring of serum 5-FC concentration and renal function, the dose-related toxic effects of 5-FC on the marrow can be avoided.

Zalcitabine Compared with Zidovudine in Patients with Advanced HIV-1 Infection Who Received Previous Zidovudine Therapy

Zidovudine (3-azido-3-deoxythymidine [AZT]) prolongs survival and decreases the frequency of and time to development of the acquired immunodeficiency syndrome (AIDS) [1-3]. Anemia and neutropenia are the most common serious toxicities associated with zidovudine therapy and may limit treatment in some patients with advanced disease [2-4]. In patients with advanced human immunodeficiency virus type 1 (HIV) infection, long-term treatment with zidovudine is associated with a progressive decline in CD4 lymphocyte counts, disease progression, increasing fatality, and emergence of virus isolates with reduced in vitro susceptibility to zidovudine [1, 5-7]. Therefore, alternative treatments for patients with progressive HIV disease are needed. Zalcitabine (dideoxycytidine [ddC]) is another deoxynucleoside analog that inhibits the in vitro replication of HIV [8] and improves certain measures of HIV infection, including the CD4 lymphocyte count and the p24 antigen level [9, 10]. In addition, zidovudine-resistant isolates are susceptible to zalcitabine in vitro [11]. The major toxicity associated with zalcitabine differs from that seen with zidovudine and includes a dose-limiting peripheral neuropathy [9, 10]. These observations prompted us to study the safety and efficacy of zalcitabine among patients with advanced HIV disease who had received previous zidovudine therapy for 48 weeks or more. Figure 1. Estimated distributions of the time to the first critical event, including AIDS-defining opportunistic infection, malignancy, or death. Methods Patients The study sample consisted of patients who had tolerated 48 weeks or more of zidovudine therapy (total daily dose 500 mg) and who had a first episode of Pneumocystis carinii pneumonia or advanced AIDS-related complex at the time of initiation of zidovudine therapy. All patients had to be receiving and tolerating zidovudine at the time of enrollment in the study. Advanced AIDS-related complex was defined by the presence of oral candidiasis, oral hairy leukoplakia, herpes varicella infection, unintentional weight loss exceeding 10% of body weight or 4.5 kg (10 lb), unexplained diarrhea (defined as two or more liquid stools per day persisting for 30 days or more) or unexplained fever (defined as a temperature greater than 38.5 C occurring for more than 14 consecutive days or for more than 15 days in a 30-day period), and a CD4-lymphocyte count of less than 200 cells/mm3. The criteria for eligibility also included a hemoglobin concentration of 95 g/L or more, a total granulocyte count of 0.750 109/L or more, a platelet count of 75 109/L or more, serum transaminase levels no higher than five times the upper limit of normal, a Karnofsky performance score of 60 or more, and seropositivity for HIV antibody as determined by any licensed enzyme-linked immunosorbent assay. At least 20% of the patients were also required to have a serum HIV p24 antigen level of 70 pg/mL or more. Patients were also excluded from the study for the following reasons: interruption of previous zidovudine therapy for more than 30 consecutive days or a total of 90 days, development of a serious toxicity during zidovudine therapy, previous zalcitabine therapy, the presence of visceral or symptomatic Kaposi sarcoma requiring therapy, the presence of peripheral neuropathy, or pregnancy. All patients received inhaled pentamidine isethionate, 300 mg every 4 weeks, for the prevention of P. carinii pneumonia. Maintenance therapy for other AIDS-related opportunistic infections was allowed. The use of other antiretroviral drugs, biologic-response modifiers, systemic corticosteroids, drugs that could cause peripheral neuropathy other than isoniazid, and experimental drugs was not allowed. The patients were recruited from four AIDS Clinical Trials Units, five university-affiliated medical centers, and private practice groups. The study was approved by institutional review boards at each center, and all patients gave written informed consent. Study Design and Treatment Regimen The study was an open-label, randomized trial. Patients were stratified according to a diagnosis of AIDS or advanced AIDS-related complex at the time of initiation of zidovudine therapy and according to the dose of zidovudine that they were receiving at study entry. The intended sample size was 160 patients per treatment arm, the number required to detect a 15% difference in survival outcome with a power of 80% and a two-sided significance level of 0.05. After the enrollment of only 115 patients, the study was closed to enrollment in July 1991 because of slow accrual. A blocked randomization procedure was used to assign patients in each center to zalcitabine or zidovudine. Zalcitabine (Hivid, Hoffmann-La Roche, Nutley, New Jersey) was given in two 0.375-mg tablets every 8 hours. Zidovudine (Retrovir, Burroughs Wellcome, Inc., Research Triangle Park, North Carolina) was initially given in two 100-mg capsules every 4 to 5 hours and then in one 100-mg capsule every 4 to 5 hours. Management of Toxicity If a serious toxicity occurred, therapy with the study medication was interrupted. After abnormal values returned to levels indicating a lower-grade toxicity or to pretreatment values, therapy with the study medication was restarted at half the dose. If severe anemia developed, red-cell transfusions or therapy with recombinant erythropoietin was administered. If patients had a toxicity that was persistent, recurred after reduction of study medication, or was life threatening, their study medication was permanently withdrawn. Zalcitabine therapy was permanently discontinued in patients who developed severe treatment-related peripheral neuropathy. Severe peripheral neuropathy was defined as moderate discomfort associated with the loss of a deep tendon reflex, the presence of paresthesias, or pain that either was refractory to non-narcotic analgesics, amitriptyline, or clonazepam or worsened during a 1-week period. Evaluation of Patients The pretreatment evaluation included a medical history, a physical examination, a signs-and-symptoms questionnaire, an evaluation for peripheral neuropathy, a Karnofsky performance score, and laboratory studies. Lymphocyte phenotyping was done by flow cytometry at the same laboratory at each center on peripheral blood mononuclear cells prepared on a Ficoll-Hypaque gradient or by the whole-blood lysis method with monoclonal reagents. The serum specimens collected for HIV p24 antigen determinations were frozen for batch testing with a commercial test kit (Abbott, North Chicago, Illinois). All patients were re-evaluated every 2 weeks for the first 12 weeks and every 4 weeks thereafter. Patients who discontinued therapy with the study medication were followed for survival only. Clinical measures of efficacy were survival and time to a first critical event, which was defined as any AIDS-related condition or death. Secondary measures of efficacy were increases in CD4 lymphocyte counts, reduction of serum p24 antigen levels, weight gain, and changes in Karnofsky performance scores. Statistical Analysis Differences in proportions were assessed using the Fisher exact test. Time-to-event distributions were estimated using the method of Kaplan and Meier and compared using the Cox proportional-hazards regression model. To assess changes in the CD4 lymphocyte count, the serum p24 antigen level, weight, and Karnofsky performance score, parametric analyses of covariance were used. Subgroup analyses were carried out, with patients stratified according to diagnosis (AIDS or AIDS-related complex) and pretreatment CD4 lymphocyte count ( 100 cells/mm3 or >100 cells/mm3). All analyses were based on an intent-to-treat approach, using clinical data available through 15 June 1991 and survival data collected through 31 December 1991. The hazard ratio expressed as relative risk and 95% two-sided CIs are given when appropriate. All P values were two sided. Results Patient Sample Between January 1990 and June 1991, 111 patients were enrolled in the study. Patients included 110 men and 1 woman (mean age, 36 years). Most patients were white and non-Hispanic. One hundred six patients were homosexual or bisexual, 7 had a history of intravenous drug use, 12 had a history of receipt of blood products, and 8 had heterosexual contact with a person at risk for HIV infection. Twenty-two patients had AIDS and 89 had AIDS-related complex at the time zidovudine therapy was first instituted. Fifty-nine patients were randomly assigned to receive zalcitabine and 52 to receive zidovudine. No significant differences were noted between the two treatment groups regarding pretreatment characteristics (Table 1). The median duration of study treatment was 279 days (range, 16 to 437 days) for the zalcitabine group and 174.5 days (range, 8 to 400 days) for the zidovudine group. The time to discontinuation of study medication was statistically shorter in the zidovudine group compared with the zalcitabine group (P = 0.001). Table 1. Patient Characteristics by Treatment Group* Of the 111 patients enrolled, 56 were withdrawn from the study medication, 20 completed the study, and 35 were still receiving study medication when the database was closed for analysis on 15 June 1991. The reasons for discontinuation of study medication included treatment with nonallowed medications (5 patients in the zidovudine group); death (2 patients in the zalcitabine group and 1 patient in the zidovudine group); toxicity (12 patients in the zalcitabine group and 5 in the zidovudine group); self-withdrawal (6 patients in the zalcitabine group and 18 in the zidovudine group); loss to follow-up (2 patients in the zalcitabine group and 3 in the zidovudine group); and administrative reasons (2 patients in the zidovudine group). Significantly more patients were withdrawn from the zidovudine group than from the zalcitabine group (34 patients compared with 22 patients; P = 0.004). For patients who complet

The continuing utility of bronchoalveolar lavage to diagnose opportunistic infection in AIDS patients

PURPOSE To determine whether bronchoalveolar lavage (BAL) remains a useful technique in assessing human immunodeficiency virus (HIV)-infected patients with pulmonary symptoms. PATIENTS AND METHODS All HIV-infected patients with pulmonary symptoms referred to a university hospital-based pulmonary service underwent bronchoscopy and BAL within 24 hours of referral. All samples were handled in a standardized fashion. The results of the lavage were compared with chest roentgenograms and clinical results. RESULTS A total of 894 lavages were performed on HIV-infected patients over a 7-year period. The overall diagnostic yield was 60%, with 420 patients having Pneumocystis carinii. Infections other than P carinii were found in 185 cases, including 75 lavages with P carinii and another infection. The other infections included Mycobacterium tuberculosis (17 patients), Mycobacterium kansasii (15 patients), Histoplasma capsulatum (24 patients), Cryptococcus neoformans (17 patients), and bacterial infection (103 patients). For 364 lavages, no diagnosis was made. Chest roentgenograms were not useful in predicting what infection would be diagnosed. There was no difference in the yield of BAL over the 7-year period, despite the introduction of aerosol pentamidine prophylaxis and antiretroviral therapy. CONCLUSION Bronchoscopy with BAL continues to have a role in the evaluation of HIV-infected patients with pulmonary symptoms.

Placental transfer of ganciclovir in a woman with acquired immunodeficiency syndrome and cytomegalovirus disease

A pregnant woman with AIDS developed cytomegalovirus (CMV) retinitis and pneumonitis, requiring intravenous ganciclovir. At 34 weeks gestation the woman delivered a 1.4-kg girl. Examination of the placenta revealed transplacental passage of CMV. Low concentrations of ganciclovir were detected in the neonates plasma. The neonate had mild anemia but no other signs of congenital CMV infection.

Simple assay for 5-fluorocytosine in the presence of amphotericin B.

A simple method for the measurement of 5-fluorocytosine in the presence of amphotericin B is described. The antifungal activity of amphotericin B is abolished by heating serum at 100 C for 45 min. 5-Fluorocytosine is unaffected by this treatment, and serum levels can be subsequently assayed by either tube dilution or disk diffusion methods.

HIV disease in primary care

During the past decade, a large number of new drugs for treating HIV and its complications have been developed. The increasingly sophisticated use of these drugs in combination has led to a marked reduction in HIV-related morbidity and mortality in countries where they are available. HIV/AIDS patients receiving treatment are now expected to live into old age. The beneficial effect of HIV treatment has resulted in an expanding population of persons living with HIV/AIDS who will need the care of an HIV specialist because of the complexity of the treatment regimens and the rapidly changing HIV/AIDS knowledge base. However, this growing and aging population will also benefit from the care of a primary care physician. The primary care generalist is in the best position to recognize and diagnose HIV infection, evaluate HIV risk in his or her patient population, and help prevent HIV infection in persons at risk. In patients known to be infected, the primary care generalist will be best able to manage hyperlipidemia, diabetes, cardiovascular disease, and other disorders of an aging population with an increased risk of these and other conditions. Patients with HIV infection frequently accumulate a large number of specialist physicians, and the unique ability of the primary care physician to monitor their care and act as a knowledgeable patient advocate is a great benefit to the patient.