Experience with a cross-study endpoint review committee for AIDS clinical trials. Terry Beirn Community Programs for Clinical Research on AIDS.

OBJECTIVES: To describe the methods and results of a standardized system for clinical endpoint determination for defining and reviewing endpoints in clinical trials for HIV-infected individuals. DESIGN: A system was developed utilizing standard definitions for the 24 diagnoses or clinical events that serve as trial endpoints and together define the combined endpoint 'progression of HIV disease. A common set of case report forms were used for all trials. Thus, an event of Pneumocystis carinii pneumonia (PCP), for example, for a subject co-enrolled in an antiretroviral trial and a PCP prophylaxis trial was only reported once. METHODS: A central committee was established to define clinical events and review endpoints across all studies. Events were classified according to established criteria for confirmed, probable and possible levels of certainty. RESULTS: This report describes the methods used to ascertain and review endpoints, and summarized 2299 clinical events for 8097 subjects enrolled in one or more of nine clinical trials. Data on the diagnostic certainty of events and agreement between site clinicians and the endpoint committee are presented. CONCLUSIONS: Uniform classification of endpoints across AIDS clinical trials can be accomplished by multicenter, multitrial organizations with standardized definitions and review of endpoint documentation. Our experience suggests that nurse coordinators reviewing all submitted endpoints for every trial are warranted and the need for external review by a clinical events committee may depend on the type of trial conducted.

Effect of oral dextran sulfate on the mouse intestinal tract.

Oral dextran sulfate is associated with adverse intestinal effects, including severe diarrhea, in some AIDS patients. We therefore investigated the intestinal flora and the intestinal histology of mice given drinking water supplemented with 8 mg/ml of dextran sulfate. There were no noticeable alterations in the major groups of intestinal bacteria in mice given oral dextran sulfate for 7 days. Likewise, there was no abnormal pathology in the ilea or colons of mice treated for 7 days with oral dextran sulfate. However, after 21 and 38 days, there was a noticeable overgrowth of facultative gram-negative bacilli in the colonic and cecal flora of dextran sulfate-treated mice. This overgrowth appeared to be due to bacterial species in the family Enterobacteriaceae, primarily Escherichia coli. Bacterial overgrowth was accompanied by mild histological alterations in the intestinal mucosa, i.e., blunting of ileal villi and colonic crypts, with mild epithelial cell dysplasia. Thus, oral dextran sulfate was associated with quantitative changes in the mouse intestinal flora, as well as histological changes in the intestinal mucosa.

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.

Increasing CD8+ T lymphocytes predict subsequent development of intraoral lesions among individuals in the early stages of infection by the human immunodeficiency virus.

Determining the progression of human immunodeficiency virus (HIV) type 1 infection based on cellular and clinical markers has become increasingly important. Although a number of studies have shown a relationship between the presence of certain oral lesions and progression to AIDS, few data exist regarding the association with T lymphocyte counts. In this study, the question of whether intraoral lesions preceded or were the consequences of changes in T lymphocyte counts was examined. A total of 116 HIV-infected patients participating in two randomized double-blind placebo-controlled trials of zidovudine at the University of Minnesota AIDS Clinical Trials Unit (ACTU) were enrolled in a prospective dental study. Patients were examined for the presence of hairy leukoplakia, candidiasis, herpes simplex, herpes zoster, aphthae, atypical gingivitis, HIV-associated periodontitis, and necrotizing ulcerative gingivitis, as well as other oral lesions, every 3 months for a maximum of four examinations over a 1-year period. T lymphocyte counts before and after each patient's oral examination were obtained. No significant differences were found at examination 1 for differences in gender, race, age, education, tobacco smoking status, ethanol consumption habits, duration in ACTU drug protocol, duration in dental study protocol, or mean T lymphocyte counts between individuals with or without oral lesions at any time in the dental study.(ABSTRACT TRUNCATED AT 250 WORDS)

Psychological effects of participation and nonparticipation in a placebo-controlled zidovudine clinical trial with asymptomatic human immunodeficiency virus-infected individuals.

Psychological effects of participation in Protocol 019, a zidovudine placebo-controlled clinical trial, were investigated. Forty-six Protocol 019 subjects and 27 control asymptomatic human immunodeficiency virus-seropositive subjects were assessed at entry, 2 months, 6 months, and after trial modification. At baseline there were no psychological differences. Most Protocol 019 and control subjects were depressed on at least one psychological measure; fewer were anxious. Both groups had improvement over time. By 6 months, Protocol 019 subjects had decreased Beck Depression Inventory (BDI) scores, state anxiety, stress reaction, and symptoms of depression and anxiety. Controls had decreased scores on only the BDI. Over time, the percentage meeting modified DSM III-R criteria for anxiety decreased in both groups and the proportion of Protocol 019 subjects meeting DSM III-R depression criteria decreased. After protocol modification, study subjects were less depressed and distressed than controls. Protocol 019 subjects reduced depression symptoms but controls did not. Clinical trial participation was not deleterious and may have yielded some relative psychological benefit.

Aspergillus osteomyelitis. Report of four cases and review of the literature.

Four cases of Aspergillus osteomyelitis are presented and the world literature is reviewed, for a total of 19 cases. Aspergillus osteomyelitis is largely a disease of immunosuppressed hosts, although wound and other infections in "normal" hosts are seen. In children, contiguous spread from an adjacent pulmonary infection is most common, whereas in adults hematogenous spread is the rule. The survival rate in immunocompromised patients is poor, whereas the cure rate is uniform in "normal" hosts. A combined medical-surgical therapeutic approach has been used most often and seems appropriate.

Extrinsic risk factors for pneumonia in the patient at high risk of infection.

Most nosocomial pathogens cause pneumonia through the following sequence: transit to the patient on the hands of medical personnel or perhaps in food, proliferation in the nasopharynx, and subsequent pulmonary aspiration. There are three exceptional pathogens, each of particular concern as a cause of pneumonia in the immunocompromised patient, which follow atypical routes. Important recent advances in understanding these routes permit more rational preventive measures. This report examines the evidentiary basis for the following pathophysiolgic propositions about these three pathogens: Aspergillus, Pneumocystis carinii, and Legionella. Aspergillus spores are almost ubiquitous. Spore generation, except in very unusual circumstances, takes place outside the hospital. Most spores enter the hospital borne in air by infiltration or because of incomplete filtration. Air filtration systems of moderate efficiency remove Aspergillus spores. Nosocomial pulmonary and disseminated aspergillosis arises from inhalation of airborne spores. A nasopharygeal colonization intermediate step before pulmonary disease has not yet been solidly established. It is now firmly established that airborne Pneumocystic carinii transmission occurs between animals. Airborne acquisition probably occurs early in human life. However, in-hospital, person-to-person transmission has yet to be convincingly demonstrated. Most or all cases of pneumocystosis in adults are due to reactivation of endogenous pulmonary organisms. Intensive diagnostic efforts reveal that Legionella is a common cause of community-acquired and nosocomial pneumonia in hospitals where it had not previously been recognized. However, there are at least a few hospitals where it is an uncommon source of pneumonia. Several hospitals have demonstrated a temporal association between the presence of Legionella in hot water systems and nosocomial cases of Legionella pneumonia. The mechanism or mechanisms of transmission to the patient remain to be delineated. It is also not determined if all hospital hot water systems should be maintained Legionella free.

Nationwide epidemic of septicemia caused by contaminated intravenous products. I. Epidemiologic and clinical features.

Between mid-1970 and April 1, 1971, Enterobacter cloacae or E. agglomerans septicemia developed in 378 patients in 25 American hospitals while they were receiving intravenous products manufactured by one company. Each of the hospitals noted a marked increase in the incidence of such septicemia during this period. Enterobacter agglomerans (formerly designated Erwinia, herbicola-lathyri group) was better known as a plant pathogen and had been a human blood pathogen only rarely in the past. Septicemia caused by E. cloacae had also been uncommon.

Evaluation of two commercial tests for human immunodeficiency virus antigens in culture supernatant fluid.

Two commercial enzyme-linked immunosorbent assays (EIAs) for human immunodeficiency virus (HIV) antigens were evaluated for sensitivity and reproducibility by use of supernatant fluid from cell cultures of peripheral mononuclear cells of 18 patients with acquired immunodeficiency syndrome (AIDS) and 12 asymptomatic HIV antibody-positive patients. Both commercial assays detected HIV antigen in all cultures by day 21; however, the Abbott HIV antigen EIA (Abbott Laboratories, North Chicago, IL) detected HIV antigen three to seven days earlier in 15 of 48 cultures (31%), on the same day in 32 cultures (67%), and three days later in 1 culture (2%) when compared with the DuPont HIV antigen EIA (DuPont Laboratories, Wilmington, DE). In serial twofold dilution experiments, the Abbott HIV Ag EIA was found to have at least a twofold to eightfold increased sensitivity over the DuPont assay. Repeat testing of 15 initially positive supernatant fluids by both assays revealed that 13 of 15 and 12 of 15 were consistently positive by the Abbott and DuPont assays, respectively. The authors conclude that the Abbott EIA demonstrated better performance in this study than the DuPont EIA for detection of HIV in cell culture because of its shorter time-to-positivity and greater sensitivity.

In-hospital needlesticks and other significant blood exposures to blood from patients with acquired immunodeficiency syndrome and lymphadenopathy syndrome.

There have been no documented cases of acquired immunodeficiency syndrome (AIDS) in personnel after a prospectively recognized in-hospital blood exposure. To assess the frequency of such exposure the membership of the Association for Practitioners in Infection Control was surveyed in early June 1983. Thirty-three percent of the membership responded, accounting for 42% of U.S. hospitals with more than 250 beds. Respondents reported needlestick or other significant blood exposures to blood from patients with AIDS occurring in 157 instances and to blood from patients with lymphadenopathy syndrome in 43 instances. Nineteen and twenty of the exposures, respectively, occurred before July 1982. There are two bases for believing that AIDS will not pose a substantial risk to hospital workers: the lack of demonstrated in-hospital AIDS transmission to date and the recognition that other viruses besides the hepatitis B virus--viruses that seem to have less potential for in-hospital transmission--are equally plausible models of AIDS transmission.

Influenza B: hospital activity during a community epidemic.

During a community epidemic of influenza B, surveillance throat cultures for influenza were collected from febrile adult patients and hospital employees on three medical wards to determine the frequency and source of influenza among hospitalized patients. Twenty-five cases of influenza B (18.5% of febrile patients) were identified; no clusters of influenza-like illness occurred. The attack rate on two wards was 4.6%. Peak hospital influenza incidence followed that in the community by 1-2 weeks. Twelve of the cases were community-acquired and 13 were nosocomial. 75% of community-acquired cases had three or more common influenza B symptoms, compared with only 39% of nosocomial cases. A viral etiology of fever was suspected clinically in one-half of the cases, but influenza was specifically suspected in only one case. Two ill culture-positive nurses were identified on the job but no asymptomatic carriers were found among ward personnel. We conclude that influenza B cases were present among hospitalized patients in the absence of recognizable clusters of disease and that patients with community-acquired illness as well as nursing personnel may have introduced influenza into the hospital. Influenza B may be difficult to diagnose clinically in hospitalized patients, but viral throat cultures performed in all suspected cases should identify many infected patients.

Prevention of nosocomial aspergillosis.

Unfiltered outside air averages 1-15 pathogenic Aspergillus sp. colony forming units (cfu) m-3 although short-term fluctuations are substantial. Seasonal variation reflects increased spore prevalence during periods of greater availability of non-viable matter. In hospital, airborne spores reflect incomplete filtration, infiltration of outside air and shedding of adherent spores from introduced objects. In highly protected hospital areas supplied with air filtered at high efficiency, where aspergillus cfus may be as low as 0.01 cfu m-3, infiltration and shedding contribute a high fraction of ambient spores. Nosocomial aspergillosis occurs in linear proportion to the mean ambient hospital airborne spore content. An analysis presuming a steady-state dynamic equilibrium is imperfect because repeated sampling produces occasional high counts which violate a Poisson distribution. 'Mini-bursts' arise from disturbance of settled spores in dust, shedding spores from clothes or other subtle sources. These sources are best mitigated by increasing the air change rate. It is most important to protect bone marrow transplant patients, leukaemia and lymphoma patients undergoing intensive, potentially curative therapy. The optimal protective environments include high filtration efficiency, point-of-use filters, protection against infiltration and filter bypass, elimination of in-hospital sources, and high air change rates.

Comparative pharmacokinetics of zidovudine in healthy volunteers and in patients with AIDS with and without hepatic disease.

To understand whether disease caused by the human immunodeficiency virus (HIV) affects zidovudine disposition, we compared the drug's pharmacokinetics in six healthy volunteers; six persons with the acquired immunodeficiency syndrome (AIDS) and no evidence of gastrointestinal (nausea, vomiting, diarrhea), renal (elevated blood urea nitrogen, serum creatinine), or hepatic (elevated liver function tests) disease; and three patients with AIDS and hepatic disease. After a single oral dose of zidovudine, serial blood samples were analyzed for drug concentration by radioimmunoassay. A one-compartment oral absorption model was fit to the concentration-time data. The absorption rate constant (4.05 vs 2.11 hr-1) and time to maximum concentration (0.61 vs 1.03 hr) were significantly different in healthy volunteers versus patients with AIDS without hepatic disease. Differences in half-life, oral clearance, and area under the curve were not statistically significant. In the three patients with AIDS plus hepatic disease, clearance was reduced an average of 63%, and area under the curve was increased by a factor of 2.3. These comparative pharmacokinetic data do not support profound differences between zidovudine's disposition in healthy volunteers and individuals with AIDS; however, the differences and trends that were observed may represent an effect of HIV disease. Although the presence of hepatic disease clearly indicates a need to modify individual dosages, these pharmacokinetic data may have more generalized implications for zidovudine dosing as the relationships between drug concentration and therapeutic or toxic effects are clarified.

The effect of cimetidine and ranitidine administration with zidovudine.

STUDY OBJECTIVE: To evaluate the possibility of a drug interaction with zidovudine and histamine2-receptor antagonists in individuals infected with the human immunodeficiency virus. DESIGN: Randomized crossover study. SETTING: University-affiliated research center. PATIENTS: Six HIV-infected individuals. INTERVENTIONS: The subjects received 7-day regimens of zidovudine 600 mg/day alone, zidovudine with cimetidine 1200 mg/day, and zidovudine with ranitidine 300 mg/day. MEASUREMENTS AND MAIN RESULTS: The renal clearance of zidovudine when given alone was 0.41 L/kg/hour, and was reduced to 0.18 L/kg/hour (p = 0.002) when given with cimetidine. In the presence of cimetidine the urinary excretion of zidovudine decreased from 89.5 to 53.7 microM (p = 0.01), the urinary ratio of metabolite to parent increased from 5.16 to 9.96 (p = 0.0001), and the fraction of zidovudine converted to metabolite increased from 0.86 to 0.92 (p = 0.0025). CONCLUSION: Cimetidine presumably inhibits the renal clearance of zidovudine by competing for tubular secretion. Based on the observation that neither cimetidine nor ranitidine had a significant effect on serum concentrations of zidovudine or zidovudine glucuronide, a change in the dosage of zidovudine is not warranted.

Povidone-iodine (betadine) in the treatment of experimental Pseudomonas aeruginosa keratitis.

Topical 5% povidone-iodine for the treatment of corneal ulcers was observed in Sierra Leone, West Africa by one of us (D.J.D.). To test the efficacy of topical 5% povidone-iodine for infectious keratitis, experimental Pseudomonas aeruginosa keratitis was induced in 12 rabbits by first abrading the central 3 mm of corneal epithelium. Thirty milliliters of broth of P. aeruginosa strain ATCC 27835 (1.8 x 10(7) viable bacteria) was dropped twice on the wounded cornea. After 22 h, all corneas were clinically infected. Eight rabbits were treated with 5% povidone-iodine solution and four with 0.9% NaCl solution. All were given hourly drops. Twenty-four hours after treatment began, the central 8-mm button of the infected cornea was excised, homogenized, and serial dilutions plated onto MacConkey agar. The total number of viable Pseudomonas organisms was calculated. The treatment group had 5.2 +/- 0.4 CFUs (colony-forming units) per cornea. The control group had 4.8 +/- 0.4 CFUs per cornea (p = 0.11). The clinical scores (Hobden grading system) were 6.9 +/- 1.5 for the treated group and 7.3 +/- 2.5 for the control group (p = 0.74). There was no statistical difference between the treated and control groups. Povidone-iodine (5%) is not effective in the acute treatment of P. aeruginosa keratitis in this rabbit model.

Periodontal status of individuals in early stages of human immunodeficiency virus infection.

The purpose of this study was to evaluate the association of periodontal health and human immunodeficiency virus infection among individuals in the early stages of disease who were participating in randomized placebo-controlled clinical trials of zidovudine. Previous reports have described a rapidly progressive periodontitis and atypical gigivitis associated with late stages of infection by the human immunodeficiency virus. A health history was completed by each subject. Baseline oral examinations were completed on 97 asymptomatic patients and nine with AIDS-related complex (ARC) during their regular clinic visit. Follow-up examinations were conducted at 3-month intervals throughout the 48 weeks of the oral study. Evaluations of plaque, calculus, gingival abnormalities, caries, and periodontal disease were conducted. Periodontal measurements included plaque index (PI), gingival index (GI), bleeding index (BI), probing depth (PD), and observation for cratering, necrosis, and tooth mobility on six teeth in each patient. More than half of the subjects had visited their dentist during the previous year and had had an oral prophylaxis; less than 25% of them had had either restorative work or extractions. The mean scores for periodontal indices averaged over the course of the study in asymptomatic and ARC respectively were: PI: 0.9 (SE 0.04) and 0.9 (SE 0.08), 0.818; GI: 1.0 (SE 0.04) and 0.9 (SE 0.07), P = 0.412; BI: 0.6 (SE 0.04) and 0.4 (SE 0.07), P = 0.278; PD: 2.9 (SE 0.05) and 2.6 (SE 0.10), P = 0.140. There was no evidence of cratering, necrosis, or tooth mobility in either group. Few had calculus or dental caries. There were no clinically significant differences detected between ARC versus asymptomatic patients. Dental histories and oral examinations showed that two groups of patients in early stages of HIV-disease were in good periodontal health.

Quantitative I-123-IMP brain SPECT and neuropsychological testing in AIDS dementia.

We performed I-123-IMP SPECT brain imaging on seven mildly demented AIDS patients and seven normal subjects. In an attempt to detect and quantitate regions of decreased I-123-IMP uptake, pixel intensity histograms of normalized SPECT images at the basal ganglia level were analyzed for the fraction of pixels in the lowest quartile of the intensity range. This fraction (F) averaged 17.5% (S.D. = 4.6) in the AIDS group and 12.6% (S.D. = 5.1) in the normal group (p less than .05). Six of the AIDS patients underwent neuropsychological testing (NPT). NPT showed the patients to have a variety of mild abnormalities. Regression analysis of NPT scores versus F yielded a correlation coefficient of .80 (p less than .05). We conclude that analysis of I-123-IMP SPECT image pixel intensity distribution is potentially sensitive in detecting abnormalities associated with AIDS dementia and may correlate with the severity of dementia as measured by NPT.

Preventing HIV transmission. Strategies to protect clinicians and patients.

Human immunodeficiency virus (HIV) transmission to healthcare workers arises primarily from percutaneous injury by sharp devices recently contaminated with infected blood. The danger is small but real, and substantial effort to reduce this risk is justified. The risk of transmission to patients from HIV-infected healthcare workers is much smaller. Attempts to accommodate measures to control this risk in standard protocols has engendered considerable debate. The discrimination and loss of insurability attendant to HIV infection also complicate the application of control measures. Where possible, procedures appropriate in cases involving known HIV infection should be applied in all situations. Acquiring tuberculosis from HIV-infected patients probably presents a greater hazard to healthcare workers than becoming infected with HIV itself.