A prospective evaluation of antituberculosis therapy in patients with human immunodeficiency virus infection.

The purpose of this study was to determine the efficacy and toxicity of a standard antituberculosis regimen in patients with human immunodeficiency virus (HIV) infection. We prospectively evaluated 89 patients with tuberculosis and HIV infection at an urban medical center. Eighty-two patients received isoniazid, rifampin, and pyrazinamide, with or without ethambutol, for 2 mo, followed by isoniazid and rifampin for 7 mo. Seven patients received other regimens because of drug resistance or intolerance. Therapy was self-administered in 57 patients and directly observed in 32 cases. All patients showed rapid clinical improvement during the first month of therapy, and sputum cultures reverted to negative after 3 mo in 52 of 54 patients from whom specimens were obtained. Adverse reactions to isoniazid or rifampin prompted alterations in antituberculosis regimens in five patients (6%). Forty patients (45%) died during follow-up, and tuberculosis was a potential contributory cause of death in three cases. Treatment failure occurred in five patients (6%), four of whom were noncompliant with therapy. The fifty patient had an isoniazid-resistant organism. No relapses occurred in 916 patient-months of follow-up posttreatment. We thus conclude that the 9-mo regimen used for treatment of drug-susceptible tuberculosis in HIV-infected patients is effective and well tolerated.

Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection.

To evaluate the relationship between the clinical presentation of tuberculosis and the CD4 cell count in patients with human immunodeficiency virus (HIV) infection, we evaluated clinical and laboratory features of 97 HIV-infected patients with tuberculosis in whom CD4 cell counts were available. Extrapulmonary tuberculosis was found in 30 (70%) of 43 patients with < or = 100 CD4 cells/microL, 10 (50%) of 20 patients with 101 to 200 CD4 cells/microL, seven (44%) of 16 patients with 201 to 300 CD4 cells/microL, and five (28%) of 18 patients with > 300 CD4 cells/microL (p = 0.02). Mycobacteremia was found in 18 (49%) of 37 patients with < or = 100 CD4 cells/microL, three (20%) of 15 patients with 101 to 200 CD4 cells/microL, one (7%) of 15 patients with 201 to 300 CD4 cells/microL, and none of eight patients with > 300 CD4 cells/microL (p = 0.002). Acid-fast smears were more often positive in patients with low CD4 cell counts. Positive tuberculin skin tests were more common in patients with high CD4 counts. On chest roentgenograms, mediastinal adenopathy was noted in 20 (34%) of 58 patients with < or = 200 CD4 cells/microL and four (14%) of 29 patients with > 200 CD4 cells/microL (p = 0.04). Pleural effusions were noted in six (10%) of 58 patients with < or = 200 CD4 cells/microL and eight (28%) of 29 patients with > 200 CD4 cells/microL (p = 0.04). The CD8 cell counts did not correlate with the manifestations of tuberculosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome. Members of the ACTG 077p/ANRS 009 Study Team.

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.

Alternating and intermittent regimens of zidovudine and dideoxycytidine in patients with AIDS or AIDS-related complex.

OBJECTIVE: To determine whether alternating regimens consisting of zidovudine and 2',3'-dideoxycytidine (ddC) reduce the toxicity and maintain or increase the antiretroviral effect associated with each drug alone. DESIGN: An unblinded, randomized (phase II) clinical trial in which seven treatment regimens were compared. SETTING: Outpatient clinics of 12 AIDS Clinical Trials Units. PATIENTS: One hundred thirty-one patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and serum p24 antigenemia (> or = 70 pg/mL). INTERVENTION: Treatments included weekly or monthly alternating zidovudine (200 mg every 4 hours) and ddC (0.01 or 0.03 mg/kg body weight every 4 hours); weekly intermittent zidovudine, 200 mg every 4 hours, or ddC, 0.03 mg/kg every 4 hours; and continuous zidovudine. MEASUREMENTS: Toxicity, CD4 cell counts, serum p24 antigen levels, and clinical end points. Data were analyzed for the first 48 weeks of therapy (median follow-up, 40 weeks). RESULTS: Hematologic toxicity was significantly less frequent in patients who received zidovudine therapy every other week (11% to 15%) or every other month (11% to 14%) than in those who received continuous zidovudine therapy (33%) (P < 0.02). Weekly alternating therapy with zidovudine and ddC, 0.03 mg/kg, or intermittent therapy with ddC, 0.03 mg/kg, produced high rates of peripheral neuropathy (41% and 50%, respectively). Neuropathy occurred in 10% to 21% of patients in the other three alternating-therapy limbs and in 17% of patients receiving zidovudine alone (intermittently or continuously). Initial increases in CD4 cell counts were sustained in three alternating-therapy limbs, but counts returned to baseline by week 28 in the remaining limbs. The median weight gain at week 48 was significantly greater in patients treated with alternating regimens (0.9 to 3.8 kg) compared with those treated with continuous zidovudine therapy (-0.7 kg) (P = 0.008). Patients treated with alternating regimens and those treated with continuous zidovudine had similarly sustained decreases in p24 antigen levels. CONCLUSIONS: These findings suggest that alternating therapy with zidovudine and ddC reduces the toxicity associated with each drug alone while maintaining strong antiretroviral activity.

Combined toxicity of zidovudine and antituberculosis chemotherapy.

Because antituberculosis agents and zidovudine are commonly used in HIV-infected patients, we performed a cohort study to determine the toxicity of such combined therapy. A group of 24 consecutive human immunodeficiency virus (HIV)-infected patients with tuberculosis who received concomitant antituberculosis therapy and zidovudine (tuberculosis group) were compared with 24 patients who received zidovudine but not antituberculosis medications (comparison group). Comparison patients were matched to tuberculosis patients by age, sex, ethnic group, month of starting zidovudine, and CD4 cell count. Most tuberculosis patients received isoniazid, rifampin, pyrazinamide, and ethambutol initially, followed by isoniazid and rifampin for a mean total duration of 8.4 months. Baseline clinical and laboratory parameters in tuberculosis and comparison patients were similar, except for the mean hemoglobin (11.2 g/dl in tuberculosis patients versus 12.9 g/dl in comparison patients, p = 0.03). The mean zidovudine dose in tuberculosis and comparison patients was approximately 500 mg/day, and the mean duration of zidovudine therapy was 10.3 and 9.6 months, respectively. Symptoms occurred during therapy with similar frequency in both groups. The frequency and severity of leukopenia and granulocytopenia were similar in tuberculosis and comparison patients, but marked anemia (hemoglobin less than 9.5 g/dl) developed in 50% of tuberculosis patients and 17% of comparison patients (p = 0.03). The maximum decrease in hemoglobin during therapy was similar in both groups (mean of 2.0 versus 1.6 g/dl, respectively), suggesting that the higher frequency of marked anemia in tuberculosis patients was due to their lower baseline hemoglobin values. Although transfusions were required in five tuberculosis patients and one comparison patient, zidovudine was not permanently discontinued in any patient because of anemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of toxoplasmic encephalitis in patients with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. The California Collaborative Treatment Group.

OBJECTIVE: To compare pyrimethamine plus clindamycin (PC) to pyrimethamine plus sulfadiazine (PS) as a treatment for toxoplasmic encephalitis (TE) in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Randomized, unblinded phase II, multicenter trial with provision for crossover for failure or intolerance of the assigned regimen. SETTING: University hospitals. PATIENTS: Eighty-four patients with presumptive TE were entered. Thirteen were excluded when they were found to have another diagnosis, and 12 were excluded because they did not meet entry criteria. The baseline characteristics in the remaining 26 patients randomized to PC and 33 randomized to PS were comparable. INTERVENTIONS: Patients were treated for 6 weeks with pyrimethamine and folinic acid plus either sulfadiazine or clindamycin. Clindamycin was given intravenously during the first 3 weeks. MEASUREMENTS AND MAIN RESULTS: There was a trend toward greater survival in patients randomized to PS (hazard ratio, 3.25; 95% CI, 0.63 to 16.8; P = 0.13), but most study deaths were not directly related to TE. In contrast, patients randomized to PC appeared more likely to achieve complete clinical (odds ratio, 0.67; CI, 0.2 to 1.97; P greater than 0.2) and radiologic responses (odds ratio, 0.28; CI, 0.08 to 0.96; P = 0.02). Multivariate analysis revealed drug effects to be largely independent of other variables. Similar efficacy of the treatments was also suggested by a hazard analysis of resolution of abnormal mental status, fever, and headache. Skin rash was the most common adverse event in both treatment arms. Because of toxicity, six patients randomized to PC and 11 patients randomized to PS had to switch to the alternate treatment, but only three were unable to complete therapy after crossover. CONCLUSIONS: The results of several end points of efficacy, taken together, suggest that the relative efficacy of PC approximately equals that of PS. PC appears to be an acceptable alternative in patients unable to tolerate PS.

Acetaminophen does not impair clearance of zidovudine.

OBJECTIVE: To determine whether concurrent treatment with acetaminophen and zidovudine impairs clearance of zidovudine, thereby increasing the risk for zidovudine-induced hematologic toxicity. DESIGN: Dose escalation, drug interaction study. SETTING: University clinical research center. PATIENTS: Patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex. INTERVENTIONS: Acetaminophen and 200 mg of zidovudine simultaneously every 4 hours. For 13 patients, the unit dosage of acetaminophen was 325 mg for 3 days; for 8 patients, the dosage was 650 mg for 3 days; and, for 6 patients, the dosage was 650 mg for 7 days. MEASUREMENTS: Zidovudine clearance and production of the glucuronide conjugate of zidovudine were assessed after acetaminophen treatment. MAIN RESULTS: Neither zidovudine clearance nor production of the glucuronide conjugate of zidovudine was impaired after treatment with acetaminophen. Clearance of zidovudine was actually accelerated by 5%, 11%, and 33% with the three acetaminophen regimens, respectively (P = 0.002 by analysis of variance; P = 0.04 for linear trend when changes in the area-under-the-curve for zidovudine were compared). CONCLUSION: Because serum concentrations of zidovudine decrease after the coadministration of acetaminophen, a pharmacokinetic interaction between zidovudine and acetaminophen is unlikely to increase the risk for hematologic toxicity associated with zidovudine.

Treatment of acute toxoplasmosis with intravenous clindamycin. The California Collaborative Treatment Group.

The interim results are presented of an ongoing large-scale, prospective, randomized study to determine the potential role of clindamycin in the treatment of toxoplasmic encephalitis. Patients were seropositive for Toxoplasma gondii antibodies and had clinical signs compatible with toxoplasmic encephalitis. Data was available on 33 patients, 15 of whom received pyrimethamine p.o./clindamycin i.v. and then p.o., and 18 of whom received pyrimethamine p.o./sulfadiazine p.o. The interim evaluation did not reveal a remarkable difference between the two regimens in the clinical or radiologic response. Adverse reactions to both regimens were common and frequently multiple, there being more adverse gastrointestinal reactions in patients on pyrimethamine/clindamycin and more adverse hematological reactions in those on pyrimethamine/sulfadiazine.

An open-label, dose-ranging trial of AL 721 in patients with persistent generalized lymphadenopathy and AIDS-related complex.

AL 721, a lipid mixture with reported in vitro activity against human immunodeficiency virus (HIV) via cell membrane or virion cholesterol depletion, was evaluated in a multicenter, open-label, dose-ranging trial. Forty men with persistent generalized lymphadenopathy or AIDS-related complex were treated with doses of 20, 30, 40, or 50 g orally twice daily for 8 weeks, and monitored for toxicity, disease progression, and with immunologic, virologic, and serum lipid profiles. The compound was found to be well tolerated over the broad range of doses examined; adverse reactions were confined to the gastrointestinal tract, of mild to moderate severity, and self-limited in duration. Modest weight gains observed on treatment were reversed within 4 weeks following cessation of therapy. While disease progression was not observed in this short-term study, we could find no indication of an immunorestorative or antiviral effect of AL 721, as determined by T-lymphocyte subset quantitation or HIV culture. All three patients who were HIV p24 antigenemic at entry retained positive antigen levels throughout treatment. As a consequence of therapy, however, significant increases in serum lipids were observed, including elevations in both triglyceride and total cholesterol levels. In conclusion, our experience on the largest group of HIV-infected patients treated with the highest doses of AL 721 provides no support for the use of this compound as an antiretroviral agent.

Undiagnosed tuberculosis in patients with human immunodeficiency virus infection.

We describe the clinical features of 11 patients with human immunodeficiency virus infection in whom tuberculosis was undiagnosed and untreated prior to death. Most patients (9 of 11) had pulmonary complaints and 8 of 11 had roentgenographic findings suggestive of tuberculosis (hilar or mediastinal adenopathy, pleural effusion, apical infiltrate or miliary pattern). Despite these findings, tuberculin skin tests were not performed in any of the patients. Acid-fast smears of sputum were obtained in three cases and bronchoscopy performed in only four, reflecting the low index of suspicion for tuberculosis. Pneumocystis carinii pneumonia was the presumptive diagnosis in nine cases but was confirmed in only one case. Autopsy revealed tuberculosis as the cause of death in four patients. Of the seven patients who did not undergo autopsy, disseminated tuberculosis, manifest by mycobacteremia, was the only life-threatening illness identified and probably contributed to death. Increased awareness of the clinical and roentgenographic features of tuberculosis in HIV-infected patients, combined with more intensive use of acid-fast smears and tuberculin skin testing, are necessary in order to decrease mortality from this treatable complication of HIV-infection.

Pleuritis as a manifestation of reactivation tuberculosis.

PURPOSE: The purpose of this study was to determine the frequency with which tuberculous pleuritis is a manifestation of reactivation tuberculosis and to compare the clinical manifestations of reactivation tuberculous pleuritis with "classic" tuberculous pleuritis, in which chest roentgenograms reveal no parenchymal infiltrates. PATIENTS AND METHODS: We evaluated the medical records of 59 patients in whom tuberculous pleuritis was confirmed by histologic findings or mycobacterial culture. Twenty-seven patients (46%) had typical chest roentgenographic findings of reactivation tuberculosis, whereas 32 (54%) had classic tuberculous pleuritis. The clinical and laboratory features of these two groups were compared. RESULTS: Symptoms were more prolonged and pleural fluid glucose and lactate dehydrogenase concentrations were more markedly abnormal in patients with reactivation pleuritis than in those with classic pleuritis, suggesting a more chronic inflammatory process in the former group. Compared with patients with classic tuberculous pleuritis, those with reactivation pleuritis had a lower frequency of reactive tuberculin skin tests (61% versus 88%) and granulomatous pleural inflammation (25% versus 72%), but a higher bacillary burden, manifest by a higher frequency of positive sputum smears for acid-fast bacilli (50% versus 0%) and positive mycobacterial cultures from sputum (60% versus 23%) and pleural fluid (91% versus 66%). CONCLUSIONS: In contrast to previous reports, tuberculous pleuritis was a manifestation of reactivation tuberculosis in 46% (27 of 59) of patients. Tuberculous pleuritis is a more chronic process in patients with reactivation disease than in those with classic pleuritis. The lower frequency of reactive tuberculin skin tests and granuloma formation, combined with the higher bacillary burden in patients with reactivation pleuritis, suggest that these patients mount a less effective immune response to Mycobacterium tuberculosis infection than do patients with the classic form of tuberculous pleuritis.

A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. The AIDS Clinical Trials Group.

BACKGROUND: The initially tested dose of zidovudine for the treatment of patients with advanced disease caused by the human immunodeficiency virus type 1 (HIV) was 1500 mg. Although this dose is effective, it is associated with substantial toxicity. METHODS: To evaluate the efficacy and safety of a reduced dose, we conducted a randomized controlled trial in 524 subjects who had had a first episode of Pneumocystis carinii pneumonia. The subjects were assigned to receive zidovudine in either a dose of 250 mg taken orally every four hours (the standard-treatment group, n = 262) or a dose of 200 mg taken orally every four hours for four weeks and thereafter 100 mg taken every four hours (the low-dose group, n = 262). RESULTS: The median length of follow-up was 25.6 months. At 18 months the estimated survival rates were 52 percent for the standard-treatment group and 63 percent for the low-dose group (P = 0.012 by the log-rank test). At 24 months the estimated survival rates were 27 percent for the standard-treatment group and 34 percent for the low-dose group (P = 0.033). In both groups, 82 percent of the subjects had another opportunistic infection, and the length of time to that infection was similar in the two groups (P = 0.56 by the log-rank test). CD4 T-lymphocyte counts improved transiently in both groups, and serum levels of HIV antigen decreased in the subjects with antigenemia. The hemoglobin level declined to less than 5 mmol per liter (80 g per liter) in 101 subjects in the standard-treatment group and in 77 in the low-dose group (39 vs. 29 percent, P = 0.0009 by the log-rank test). The neutrophil count declined to less than 0.750 x 10(9) per liter in 134 subjects in the standard-treatment group and in 96 in the low-dose group (51 vs. 37 percent, P = 0.0001). CONCLUSIONS: The reduced daily dose of zidovudine used in this study was at least as effective as the standard dose and was less toxic; however, with the use of a four-week induction period with a high dose followed by low-dose treatment, severe anemia and neutropenia were common complications of treatment with zidovudine.

Seronegative disseminated coccidioidomycosis in patients with HIV infection.

Serologic testing for complement-fixing antibodies to Coccidioides immitis is commonly employed to assist in the diagnosis and management of this infection, but its usefulness in an HIV-coinfected population is unknown. In this study we reviewed all the mycologically or histologically proven cases of disseminated C. immitis infection after 1982. Disseminated C. immitis and proven HIV infection were present in eight patients. We performed serum complement-fixing antibody titers on all eight patients, six of whom gave positive tests, while two patients (25%) gave repeatedly negative results despite widely disseminated disease. We conclude that histopathology and culture remain the most reliable methods for the diagnosis of disseminated coccidioidomycosis in the HIV-infected host.

Acute, rapidly progressive renal failure with simultaneous use of amphotericin B and pentamidine.

We report four cases of acute reversible renal failure in patients with acquired immune deficiency syndrome who received both amphotericin B (for systemic mycoses) and pentamidine isethionate (for Pneumocystis carinii pneumonia). The concurrent use of amphotericin B with either inhaled pentamidine or trimethoprim-sulfamethoxazole did not cause significant renal impairment.

Rattlesnake capsule-associated Salmonella arizona infections.

Three Hispanic patients at our institution developed extragastrointestinal Salmonella arizona infection associated with the ingestion of rattlesnake capsules. All patients had underlying chronic medical illnesses, including the acquired immunodeficiency syndrome, systemic lupus erythematosus, and congestive heart failure. Rattlesnake capsules were obtained from both local pharmacies and patients. Salmonella arizona, as well as various other enteric organisms, was grown on cultures obtained from all capsules tested. Review of the literature disclosed three additional cases of extragastrointestinal S arizona infection linked to rattlesnake capsule ingestion, all associated with underlying medical illness. We postulate that rattlesnake capsules may be frequently ingested by chronically ill Hispanic individuals and serve as a vehicle for serious S arizona infection.