Clinical trials: to terminate or not to terminate. The VA Cooperative Studies Group on AIDS.
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Biomedical subjects
Publications and source records attributed to M S Simberkoff.
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BACKGROUND: Zidovudine is recommended for asymptomatic and early symptomatic human immunodeficiency virus (HIV) infection. The best time to initiate zidovudine treatment remains uncertain, however, and whether early treatment improves survival has not been established. METHODS: We conducted a multicenter, randomized, double-blind trial that compared early zidovudine therapy (beginning at 1500 mg per day) with late therapy in HIV-infected patients who were symptomatic and had CD4+ counts between 0.2 x 10(9) and 0.5 x 10(9) cells per liter (200 to 500 per cubic millimeter) at entry. Those assigned to late therapy initially received placebo and began zidovudine when their CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter) or when the acquired immunodeficiency syndrome (AIDS) developed. RESULTS: During a mean follow-up period of more than two years, there were 23 deaths in the early-therapy group (n = 170) and 20 deaths in the late-therapy group (n = 168) (P = 0.48; relative risk [late vs. early], 0.81; 95 percent confidence interval, 0.44 to 1.59). In the early-therapy group, 28 patients progressed to AIDS, as compared with 48 in the late-therapy group (P = 0.02; relative risk, 1.76; 95 percent confidence interval, 1.1 to 2.8). Early therapy increased the time until CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter), and it produced more conversions from positive to negative for serum p24 antigen. Early therapy was associated with more anemia, leukopenia, nausea, vomiting, and diarrhea, whereas late therapy was associated with more skin rash. CONCLUSIONS: In symptomatic patients with HIV infection, early treatment with zidovudine delays progression to AIDS, but in this controlled study it did not improve survival, and it was associated with more side effects.
Major surgical procedures, especially when performed under general anesthesia, can depress immunological parameters measured in vitro. Therefore concern has been expressed that operation might have an adverse effect on the immune status of individuals infected with the human immunodeficiency virus (HIV). Four HIV-positive patients without symptoms of HIV disease underwent cardiac valve replacement in consequence of infective endocarditis. After up to 15 months postoperatively, 3 patients are alive and well without signs of progressive immunodeficiency or recurrent endocarditis. One patient died of recurrent endocarditis without evidence of HIV-related disease on autopsy. Cardiac operation does not seem to accelerate HIV-related immunodeficiency.
Five cases of large tuberculous abscesses in patients with AIDS were observed over a 2-year period at the New York Veterans Affairs Medical Center. These cases represent 11.6% of the 43 cases of tuberculosis diagnosed in patients with AIDS during that period. The abscesses were located in the liver, abdominal wall, psoas muscle, mediastinum, and peripancreatic area. All patients presented with localized pain or swelling, and four of five patients had fever. The diagnosis was made on the basis of detection of abscesses on computed tomography (CT) and the results of culture of abscess material obtained by CT-guided aspiration. CT-guided therapeutic drainage was performed in two cases. Despite administration of therapy, two of five patients died of tuberculous infection. Formation of tuberculous abscesses appears to be a common complication of tuberculosis in patients with AIDS. This diagnosis should be considered for patients with AIDS who have fever and localized pain or swelling.
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To determine the excess mortality attributable to hospital-acquired bloodstream infections, we applied the acute physiology and chronic health evaluation (APACHE) II classification to 34 critically ill patients with this complication. The study included primary bloodstream infections, defined by a positive blood culture at least three days after hospitalization, in the absence of any other apparent source of infection. The most frequent blood isolates included Staphylococcus aureus (39 percent), Gram-negative rods (24 percent), and Candida albicans (15 percent); the spectrum of blood isolates suggested that most infections were related to intravascular catheters. In a control group of intensive care unit patients (n = 384), the death rate predicted by APACHE II was similar to the observed death rate (35.3 vs 37.8 percent). In a subgroup of control patients (n = 34), chosen for APACHE II scores that matched the patients with bloodstream infections, predicted and observed death rates were also similar (53.1 vs 52.9 percent). For patients with bloodstream infections, however, observed mortality (82.4 percent) significantly exceeded the predicted value (54.1 percent, p = 0.025). We conclude that critically ill patients who develop nosocomial bloodstream infections are at greater risk of death than patients with comparable severity of illness without this complication. The difference between the observed and predicted death rates, 28 percent, represents the excess mortality associated with bloodstream infection in critically ill patients.
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Over 91,000 cases of AIDS have been reported in United States, and it has been estimated that more than 1 million individuals are currently infected by the human immunodeficiency virus (HIV). The disease is growing most rapidly among intravenous drug abusers and minority patients. This accentuates some medical and ethical problems. Chief among these are the availability of competent care for patients and the willingness of physicians to treat these patients, issues related to HIV testing and counseling, patients' rights regarding the extent of treatment that should be given and access to and participation in clinical trials.
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Severe Pneumocystis carinii pneumonia (PCP) necessitating mechanical ventilation has been associated with a high mortality rate in several previous studies. This has discouraged physicians from recommending, as well as patients from accepting, mechanical ventilation when respiratory failure developed. Analysis of 19 records of patients with first episode PCP who were intubated and received mechanical ventilation showed a mortality of 57.8%. A constellation of clinical and laboratory findings was found that identified those patients more likely to survive, including a shorter duration of symptoms prior to admission, better arterial oxygenation on admission, deterioration of respiratory status soon after bronchoscopy, decrease in serum lactic acid dehydrogenase and rapid improvement in arterial blood gas determinations after institution of mechanical ventilation. Mean survival for the group that recovered from PCP after mechanical ventilation was not different from that of other patients with PCP who did not require mechanical ventilation. Thus, patients at risk for PCP should be advised to present to medical facilities as soon as symptoms of this disease develop and, when appropriate, should be encouraged to undergo intubation with respiratory support if it becomes necessary.
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We conducted a randomized, double-blind, placebo-controlled trial to test the efficacy of the 14-valent pneumococcal capsular polysaccharide vaccine in 2295 high-risk patients (patients with one or more of the following: age above 55 years and the presence of chronic cardiac, pulmonary, renal, or hepatic disease, alcoholism, or diabetes mellitus). Seventy-one episodes of proved or probable pneumococcal pneumonia or bronchitis occurred among 63 of the patients (27 placebo recipients and 36 vaccine recipients). Vaccine-serotype Streptococcus pneumoniae strains were recovered in association with 11 infections in the placebo group and 14 infections in the vaccine group. Pneumococcal infections occurred most frequently among patients with chronic pulmonary, cardiac, or renal diseases. Among vaccine recipients who subsequently had vaccine-type pneumonia or bronchitis, the majority did not make or sustain serum antibodies against their infecting organism in concentrations that were twice as high as the base-line values, or more than 400 ng of antibody nitrogen per milliliter, although their base-line levels were higher than those in subjects in whom infection did not develop. We were unable to demonstrate any efficacy of the pneumococcal vaccine in preventing pneumonia or bronchitis in this population. Our data suggest that chronically ill patients, who are most susceptible to infection, may have an impaired immune response to the pneumococcal vaccine.
Severe hemorrhagic pancreatitis developed in a patient with the acquired immunodeficiency syndrome (AIDS) during pentamidine isethionate treatment for Pneumocystis carinii pneumonia. Despite prompt withdrawal of administration of the drug, the patient died of complications of pancreatitis. Pentamidine is known to be toxic to pancreatic islet cells, causing both hypoglycemia and hyperglycemia in clinical use. However, it rarely causes symptomatic pancreatitis. A review of the literature indicates that this is the second report of fatal pancreatitis associated with pentamidine therapy.
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