Clinical efficacy of monotherapy with stavudine compared with zidovudine in HIV-infected, zidovudine-experienced patients. A randomized, double-blind, controlled trial. Bristol-Myers Squibb Stavudine/019 Study Group.

BACKGROUND: Stavudine is a promising antiretroviral agent, but its clinical efficacy has not been determined. OBJECTIVE: To evaluate the clinical effect of stavudine (2',3'-didehydro-3'-deoxythymidine) monotherapy in patients with human immunodeficiency virus (HIV) infection. DESIGN: Randomized, controlled, double-blind trial. SETTING: 56 outpatient clinics in private practices, universities, and contract research organizations in the United States, France, and Italy. PATIENTS: 822 HIV-infected adults who had 50 to 500 CD4+ cells/mm3 and had previously received at least 6 months of zidovudine treatment. INTERVENTION: Monotherapy with peroral stavudine capsules or peroral zidovudine capsules. MEASUREMENTS: The primary end point was clinical progression, which was defined as all occurrences of acquired immunodeficiency syndrome (AIDS)-defining events or death. RESULTS: Patients receiving stavudine reached clinical end points at a rate of 26 per 100 person-years, compared with 32 per 100 person-years for patients receiving zidovudine (relative risk, 0.75 [95% CI, 0.58 to 0.98]; P = 0.03). The risk for death alone was 26% lower in the stavudine group than in the zidovudine group, but the comparison was not statistically significant (relative risk, 0.74 [CI, 0.53 to 1.02]; P = 0.066). The benefit of stavudine therapy was seen in all CD4+ cell strata (< or = 100 cells/mm3, 101 to 300 cells/mm3, and > 300 cells/mm3) and clinical stages of HIV disease (asymptomatic, symptomatic, and AIDS). Four weeks after treatment began, CD4+ cell counts were 30 cells/mm3 higher in the stavudine group than in the zidovudine group; this difference was sustained for 96 weeks (P < 0.001). Nausea and vomiting were more common in patients receiving zidovudine (P < 0.01), and neuropathy occurred more frequently in those receiving stavudine (12% in the stavudine group compared with 4% in the zidovudine group; P < 0.001). Neuropathy resolved completely in many patients (63%) after interruption of stavudine treatment; these patients could resume stavudine therapy at a lower dose. CONCLUSIONS: Stavudine was well tolerated and delayed progression of HIV disease in patients who had previously received 6 or more months of zidovudine treatment. Benefits were apparent in all CD4+ cell strata and clinical stages of HIV disease. Stavudine is an important agent to consider for trials of combination chemotherapy.

Diagnosing and treating cytomegalovirus pneumonia in patients with AIDS.

Because cytomegalovirus (CMV) can be isolated from pulmonary secretions of human immunodeficiency virus (HIV)-infected patients without causing disease, its clinical significance as a cause of pneumonia in this patient population is frequently questioned. In a 22-month period, CMV pneumonia was diagnosed in 17 (8%) of 210 HIV-infected patients who underwent lung biopsy on the basis of microbiological and histologic criteria. The clinical presentations of these patients were nonspecific, including fever (100% of patients), shortness of breath (71%), cough (76%), and Pao2 of < 75 mm Hg (88%). A high correlation in the degree of viral burden in lung biopsy specimens was demonstrated by histologic examination, immunohistochemical analysis, and in situ hybridization. No other pulmonary pathogens were identified for nine patients, whereas other possible causes of pneumonia were present in eight: 11 patients had evidence of extrapulmonary CMV disease at presentation. Most patients initially responded to specific anti-CMV therapy; the overall mean survival +/- SD was 3.1 +/- 2.5 months. CMV should be considered as a possible cause of pneumonia in patients with advanced AIDS especially if CMV infection is documented at other sites.

Comparison of three methods for recovery of Mycobacterium avium complex from blood specimens.

Three methods were used for the recovery of mycobacteria from blood specimens obtained from acquired immunodeficiency syndrome patients: (i) inoculation of 7H11 agar plates with a concentrated specimen, (ii) inoculation of 7H12 BACTEC vials with a concentrated specimen, and (iii) inoculation of 7H13 BACTEC vials with a nonconcentrated specimen. In this study, we examined 255 specimens and obtained positive mycobacterial growth in 47 of them. Among these 47 cultures, 40 were found to be positive by all three methods, and the total recovery rates in relation to these culture-positive specimens were 94% for method 1, 89% for method 2, and 96% for method 3. The advantages and disadvantages of these three methods are discussed.

Intravitreal ganciclovir in the treatment of AIDS-associated cytomegalovirus retinitis.

Ganciclovir (BW B759U, DHPG, dihydroxy propoxymethyl guanine) was injected directly into the vitreous in 14 eyes of 11 patients with severe acquired immune deficiency syndrome (AIDS)-associated cytomegalovirus (CMV) retinitis. All 11 patients either demonstrated serious myelosuppression which precluded the continuation of intravenous ganciclovir therapy (5 patients) or were experiencing progressive CMV retinitis despite therapy with maximum-tolerable dosages of intravenous ganciclovir (6 patients). Suppression of the retinitis was observed in 11 (78%) of the 14 treated eyes. Three eyes (22%) showed no improvement after the initial intravitreal injection. One rhegmatogenous retinal detachment (RD) occurred during an injection. There were no other complications, and no intraocular drug toxicity was observed. Reactivation of CMV retinitis necessitated repeated injections in 9 (64%) of the 14 eyes. The authors' experience with these 30 intravitreal injections indicates that the procedure is safe and effective both as an alternative to intravenous ganciclovir therapy in myelosuppressed patients and as a supplement to intravenous therapy in uncontrolled CMV retinitis.

Blood selenium and glutathione peroxidase levels and dietary selenium of free-living and institutionalized elderly subjects.

The purpose of this study was to evaluate the selenium status of healthy free-living and institutionalized elderly people. For the 36 free-living elderly dietary selenium intake averaged 94 +/- 44 micrograms Se/day and a positive correlation coefficient was found between dietary selenium and dietary calories (r = 0.46; P less than 0.05), dietary protein (r = 0.60; P less than 0.01), and dietary fat (r = 0.43; P less than 0.05). Diet histories from the institutionalized subjects revealed a strong correlation coefficient between selenium and carbohydrate (r = 0.51; P less than 0.005) and selenium and calories (r = 0.44; P less than 0.05). Mean erythrocyte and plasma selenium levels for the free-living subjects were 0.20 +/- 0.06 micrograms/ml and 0.10 +/- 0.03 micrograms/ml, respectively, while mean erythrocyte glutathione peroxidase (GSH-Px) activity was 27.5 +/- 5.0 units/g protein. For the free-living subjects positive correlation was found between dietary selenium and erythrocyte selenium levels (r = 0.38; P less than 0.05) but no correlation existed between dietary selenium and plasma selenium (r = 0.13; P greater than 0.05) and RBC GSH-Px (r = -0.15; P greater than 0.05). The dietary selenium levels and blood selenium and GSH-Px levels were above the levels found in populations proposed to be at risk for selenium deficiency. Thus, these elderly appear to have adequate selenium status.

Follow-up respiratory function of a patient treated with a membrane lung.

A patient in remission from acute lymphoblastic leukemia developed the adult respiratory distress syndrome. Despite "optimal respiratory therapy" and ventilatory assistance with 100 per cent inspired O2 (fraction of inspired O2 = 1) and 15 cm of positive end-expiratory pressure, the patient's arterial PO2 remained at 33 mm Hg. Prepulmonary venovenous respiratory support was given for 10 days with a spiral coil membrane lung. The data document the sequential improvement in respiratory function and suggest that despite the severe lung damage that may occur during the adult respiratory distress syndrome treated with prolonged high inspired concentration of O2, if the patient's lungs recover from the acute process, the respiratory system can recover so that there is little, if any, permanent restriction of the subject's activities as a result of respiratory impairment.

Relative thrombogenicity of polydimethylsiloxane and silicone rubber constituents.

Medical grade silicone rubber (MGSR) is composed of polydimethylsiloxane (PDMS) as well as silica filler, oxidation products from the curing process, and other components. In a test that excludes air-blood interfaces, PDMS radiation cured under nitrogen has a whole blood clotting time 22% longer than MGSR. Curing the PDMS under oxidizing conditions maintains a 10% prolongation, but addition of silica filler to the PDMS returns the clotting time to that of MGSR. Extracting MGSR with solvents other than water appreciably lowers the clotting time. These results indicate the "pure" PDMS has an intrinsically high thromboresistance. Thrombogenicity is increased by the use of silica filler and oxidizing cure, as in MGSR.

Acute respiratory failure. Survival following ten days' support with a membrane lung.

An 11-year-old boy with acute lymphoblastic leukemia in remission developed a bilateral pneumonia which rapidly progressed to acute respiratory failure. During 9 days of intensive therapy the patient's respiratory status progressively deteriorated. When it became impossible to maintain the arterial oxygen tension (PAO2) above 40 mm.Hg by conventional means, extracorporeal blood-gas exchange with a membrane lung was begun. After 5 days of bypass the patient's respiratory function began to improve, and he was weaned from the membrane lung on the tenth day. Seven days later he was discharged from the hospital and is currently in excellemt health 23 months after bypass. This perfusion, the longest successful effort to provide respiratory assist with a membrane lung, attests to the efficacy of this therapeutic modality.