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.     

Rates of tuberculosis infection in healthcare workers providing services to HIV-infected populations. Terry Beirn Community Programs for Clinical Research on AIDS

OBJECTIVE: To assess the prevalence of tuberculosis (TB) or a positive skin test in healthcare workers (HCWs) providing services to human immunodeficiency virus (HIV)-infected individuals and to determine prospectively the incidence of new infections in this population. DESIGN: This prospective cohort study enrolled 1,014 HCWs working with HIV-infected populations from 10 metropolitan areas. Purified protein derivative (PPD) tuberculin skin tests were placed at baseline and every 6 months afterwards on those without a history of TB or a positive PPD. Demographic, occupational, and TB exposure data also were collected. SETTING: Outpatient clinics, hospitals, private practice offices, and drug treatment programs providing HIV-related healthcare and research programs. PARTICIPANTS: A voluntary sample of staff and volunteers from 16 Community Programs for Clinical Research on AIDS units. RESULTS: Factors related to prior TB or a positive skin test at baseline included being foreign-born, increased length of time in health care, living in New York City, or previous bacille Calmette-Guerin vaccination. The rate of PPD conversion was 1.8 per 100 person years of follow-up. No independent relation was found between the amount or type of contact with HIV-infected populations and the risk of TB infection. CONCLUSION: These data provide some reassurance that caring for HIV-infected patients is not related to an increased rate of TB infection among HCWs in these settings.     

Weekly fluconazole for the prevention of mucosal candidiasis in women with HIV infection. A randomized, double-blind, placebo-controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS

BACKGROUND: Candidiasis is a frequent complication of infection with the human immunodeficiency virus (HIV); however, few data exist about the natural history, prevention, and treatment of mucosal candidiasis in women. OBJECTIVE: To evaluate the safety and effectiveness of weekly fluconazole prophylaxis for mucosal candidiasis in women infected with HIV. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 14 sites participating in the Community Programs for Clinical Research on AIDS (CPCRA). PATIENTS: 323 women with HIV infection and CD4+ cell counts of 300 cells/mm3 or less. INTERVENTION: 200 mg of fluconazole per week or placebo. Open-label fluconazole for candidiasis prophylaxis was permitted after two oropharyngeal or vaginal episodes or one esophageal episode. MEASUREMENTS: Development of mucosal candidiasis, clinical and in vitro resistance of Candida species to fluconazole, survival, and adverse events. RESULTS: After a median follow-up of 29 months, 72 of 162 patients receiving fluconazole and 93 of 161 patients receiving placebo had at least one episode of candidiasis (relative risk [RR], 0.56 [95% Cl, 0.41 to 0.77); P < 0.001). Weekly fluconazole was effective in preventing oropharyngeal candidiasis (RR, 0.50 [Cl, 0.33 to 0.74]; P < 0.001) and vaginal candidiasis (RR, 0.64 [Cl, 0.40 to 1.00]; P = 0.05) but not esophageal candidiasis (RR, 0.91 [Cl, 0.48 to 1.72]; P > 0.2). Relative risks were similar for women who had a history of mucosal candidiasis (RR, 0.5 [Cl, 0.35 to 0.75]) and those who did not (RR, 0.69 [Cl, 0.35 to 1.34]). Absolute risk reduction for patients with a history of infection was 25.6 per 100 person-years, which is more than twice the reduction of 11.2 per 100 person-years seen in patients with no history of infection. This difference reflects the higher risk of patients who previously had an infection. Candida albicans was not usually resistant to fluconazole in vaginal specimens in clinical or in vitro settings; such resistance occurred in less than 5% of patients in each group. CONCLUSIONS: Weekly fluconazole (200 mg) seems to be safe and effective in preventing oropharyngeal and vaginal candidiasis. This regimen has a useful role in the management of HIV-infected women who are at risk for recurrent mucosal candidiasis.     

Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS

CONTEXT: Peripheral neuropathy is common in persons infected with the human immunodeficiency virus (HIV) but few data on symptomatic treatment are available. OBJECTIVE: To evaluate the efficacy of a standardized acupuncture regimen (SAR) and amitriptyline hydrochloride for the relief of pain due to HIV-related peripheral neuropathy in HIV-infected patients. DESIGN: Randomized, placebo-controlled, multicenter clinical trial. Each site enrolled patients into 1 of the following 3 options: (1) a modified double-blind 2 x 2 factorial design of SAR, amitriptyline, or the combination compared with placebo, (2) a modified double-blind design of an SAR vs control points, or (3) a double-blind design of amitriptyline vs placebo. SETTING: Terry Beirn Community Programs for Clinical Research on AIDS (HIV primary care providers) in 10 US cities. PATIENTS: Patients with HIV-associated, symptomatic, lower-extremity peripheral neuropathy. Of 250 patients enrolled, 239 were in the acupuncture comparison (125 in the factorial option and 114 in the SAR option vs control points option), and 136 patients were in the amitriptyline comparison (125 in the factorial option and 11 in amitriptyline option vs placebo option). INTERVENTIONS: Standardized acupuncture regimen vs control points, amitriptyline (75 mg/d) vs placebo, or both for 14 weeks. MAIN OUTCOME MEASURE: Changes in mean pain scores at 6 and 14 weeks, using a pain scale ranging from 0.0 (no pain) to 1.75 (extremely intense), recorded daily. RESULTS: Patients in all 4 groups showed reduction in mean pain scores at 6 and 14 weeks compared with baseline values. For both the acupuncture and amitriptyline comparisons, changes in pain score were not significantly different between the 2 groups. At 6 weeks, the estimated difference in pain reduction for patients in the SAR group compared with those in the control points group (a negative value indicates a greater reduction for the "active" treatment) was 0.01 (95% confidence interval [CI], -0.11 to 0.12; P=.88) and for patients in the amitriptyline group vs those in the placebo group was -0.07 (95% CI, -0.22 to 0.08; P=.38). At 14 weeks, the difference for those in the SAR group compared with those in the control points group was -0.08 (95% CI, -0.21 to 0.06; P=.26) and for amitriptyline compared with placebo was 0.00 (95% CI, -0.18 to 0.19; P=.99). CONCLUSIONS: In this study, neither acupuncture nor amitriptyline was more effective than placebo in relieving pain caused by HIV-related peripheral neuropathy.     

Cigarette smoking and other risk factors for silent cerebral infarction in the general population

Control dried organisms as lenticules are a dependable and convenient alternative to wet cultures for quality assurance and process controls in routine food microbiology. Lenticules are designed to give a fixed, reproducible inoculum over an extended period of time without loss of cultural characteristics or viability. During a period of 23 months, 596 paired counts were performed by both Miles and Misra and spiral plating techniques on lenticule controls. Correlation between the two methods and within batches was excellent. Only 14 counts (2.5%) fell outside the standard operating limit of 0.5 log10. All were within 1.0 log10. On two separate occasions, replicate runs were performed on five reconstituted lenticules from a batch. The counts obtained showed variation within and between lenticules only slightly in excess of what is expected by chance. Lenticule replicates performed by three other laboratories also produced satisfactory results. It is thought that lenticules could improve the accuracy of total plate counts and lead to a better standardization of quantitative methods in food microbiology within and between laboratories.     

Effect of night smoking, sleep disturbance, and their co-occurrence on smoking outcomes.

Recent evidence suggests that smoking during the night is an indicator of nicotine dependence and predicts smoking cessation failure. Night smokers are likely to experience disturbance to their sleep cycle when they wake to smoke, but we are not aware of the prevalence of night smokers' self-reported sleep disturbance. Because sleep disturbance also predicts smoking cessation failure, we examined how the pre-cessation risk factors of night smoking and sleep disturbance, and their co-occurrence, predict smoking cessation failure in a 6-week double-blind randomized controlled trial examining whether naltrexone augments the efficacy of the nicotine patch (O'Malley et al., 2006). Smokers (N = 385) completed the Pittsburgh Sleep Quality Index (Buysse, Reynolds, Monk, Berman, & Kupfer, 1989) and a single item of waking at night to smoke pre-cessation. Smoking status was determined at weeks 1, 6, 24, and 48 weeks after quitting. The two main findings were: (a) night smokers reported significantly greater sleep disturbance than nonnight smokers; and (b) smokers with co-occurring night smoking and sleep disturbance experienced significantly greater risk for smoking than smokers with neither risk factor. Results suggest that individuals who both wake during the night to smoke and report clinically-significant sleep disturbance represent a high-risk group of smokers. Future smoking cessation treatment might incorporate strategies related to managing these smokers' sleep habits and physiological dependence on nicotine in order to bolster their cessation outcomes. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Incidence and clinical manifestations of HIV-1 infection in multitransfused thalassaemic Indian children

Four hundred and six multitransfused thalassaemic children attending the paediatric clinic in Manipur, India, were screened for HIV antibodies. There were 46 (8.9%) ELISA antibody-positive children and the diagnosis was reaffirmed by Western blot assay. The immunologic status of the seropositive children was evaluated by a) absolute lymphocyte count, b) percentage of ratio of T helper (CD4+) and T suppressor (CD8+) cells, c) quantitative Ig, G, M and A levels and d) delayed-type cutaneous hypersensitivity (DTH) testing. Twelve of the 36 seropositive children were clinically symptomatic with AIDS. The clinical and immunological status of seropositive children are compared with matched seronegative thalassaemic control groups. Five of the 12 symptomatic seropositive children had received continued antiretroviral treatment. The mortality rate at the end of 36 weeks of itinerary was 20% in contrast to 50% in the untreated children. This report highlights the value of early recognition and therapeutic intervention in a selected high risk paediatric population.     

Clinical predictors of HIV-1 infection among preschool children in Dar es Salaam, Tanzania

Seroprevalence of HIV-1 infection was determined in children aged between eighteen months and five years, attending maternal and child health (MCH) clinics in Dar es Salaam, Tanzania. A total of 889 children were eligible for the study, however seven children could not be enrolled because their mothers/guardians absconded and blood could not be drawn from 21 children due to refusal of mothers/guardians and from another 12 children due to technical reasons. Therefore, the participation rate was 95.5%. Of the 849 children screened, 14 (1.65%) were found to have IgG anti HIV-1 antibodies in their sera. The main clinical features found in children with symptomatic HIV-1 disease were weight loss, generalized lymphadenopathy, recurrent fevers, and prolonged diarrhoea. The utility of clinical features suggestive of HIV-1 infection (according to CDC classification) in identifying HIV-1 infection in children was evaluated and found to have high sensitivity (100%), specificity (96.9%) and negative predictive value (100%), but a low positive predictive value (35%). Marked variations in progression to symptomatic phase were noted, whereby some relatively young children had progressed to symptomatic phase (CDC class P-2A), while some older children were still in the asymptomatic stage (CDC class P-1 C). None of the symptomatic HIV-1 infected children presented with neurological disease, severe opportunistic infections, or malignancies. Although reduced mid-upper arm circumference and weight-for-age were associated with HIV seropositivity, these clinical parameters had low positive predictive values compared to the CDC classification.     

Primary cutaneous cryptococcosis and bacterial pneumonia caused by Pseudomonas aeruginosa in AIDS: clinical case and review of the literature

Physicians typically assess glaucoma treatment in terms of the effect on intraocular pressure (IOP). However, it is inappropriate to use IOP as the sole outcome measure for the management of glaucoma for several reasons: a) it is a precursor of disease, but not the disease itself. b) Most often, it is not the only factor responsible for glaucomatous damage. c) It suggests, wrongly, that IOP should be maximally lowered in all glaucoma patients. d) We are beginning to be able to assess more accurately other signs, not just precursors, of glaucomatous damage itself, most importantly, optic disc damage and visual field loss. Even though these signs are far more valuable than IOP in assessing the outcome of treatment, they, too, nevertheless, are ultimately subordinate to the effect of treatment on the patient's quality of life.     

Measurement of depression and neuropsychological impairment in HIV-1 infection.

Depression and neuropsychological (NP) impairment were examined in 30 HIV-1 seropositive symptomatic, 15 seropositive asymptomatic, and 14 seronegative control participants. Items on the Beck Depression Inventory (BDI) were separated into somatic and affective components to examine effects of illness on depression. Twenty-two NP tests tapped motor and psychomotor function, cognitive flexibility, and memory. The symptomatic seropositive group had the highest mean depression scores. However, these group differences were seen with the somatic component, not the affective. No significant correlations were obtained between NP tests and the affective component. Although 3 of 11 psychomotor measures were modestly correlated with the BDI total and somatic component, depression was generally unrelated to NP performance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Computerized and traditional Stroop task dysfunction in HIV-1 infection.

Controlled processing, response inhibition, and set adoption were examined in 51 HIV-1 infected participants and 21 uninfected controls who were administered a vocal reaction time (RT) version of the Stroop task (Stroop-RT; J. R. Stroop, 1935) as well as the traditional 100 item paper-and-pencil version. Response set expectancies on the Stroop-RT were manipulated by presenting 50% of trials in homogenous blocks and randomly varying the stimulus type during the remaining trials. As hypothesized, HIV seropositive (HIV+) participants were significantly slower than HIV seronegative controls on both versions of the Stroop. Significant interference effects were apparent on the paper-and-pencil version of the Stroop, but were not as prominent on the Stroop-RT. The HIV+ participants did profit from the blocking manipulation on the Stroop-RT, suggesting that set adoption is retained in HIV infection. These data suggest that HIV infection may result in deficient response inhibition, possibly secondary to frontostriatal dysfunction and dopaminergic alterations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Unintegrated circular HIV-1 DNA in the peripheral mononuclear cells of HIV-1-infected subjects: association with high levels of plasma HIV-1 RNA, rapid decline in CD4 count, and clinical progression to AIDS

We observed 36 HIV-infected patients to evaluate whether the presence of tandem 2-long terminal repeat circular unintegrated HIV-1 DNA (2-LTR) in peripheral blood mononuclear cells (PBMC) at baseline was associated with acceleration of HIV disease. Detection of 2-LTR at baseline correlated with high plasma HIV-1 RNA levels (p < .01), recovery of culturable HIV-1 from plasma (p = .02), and progression to AIDS during follow-up (p = .01). More patients with 2-LTR (68%) than without 2-LTR (31%) had a decline in CD4 levels of >50 cells/mm3 over the first 18 months of follow-up (p = .04), and the average annual CD4 decline was 35% in patients with 2-LTR compared with 16% in those without 2-LTR (p = 0.06). Detection of 2-LTR in PBMC at baseline was an independent predictor of high plasma HIV-1 RNA levels and subsequent CD4 cell decline in this cohort of patients with predominantly nonsyncytium-inducing (NSI) isolates at baseline. The presence of 2-LTR in PBMC appears to be reflective of ongoing HIV-1 replication, as measured by plasma HIV-1 RNA levels, and identifies persons at risk for immunologic and clinical decline.     

Cigarette smoking, blood pressure and pulse rate in the Jerusalem Lipid Research Clinic Prevalence Study

The relationship between cigarette smoking and blood pressure (BP) and pulse rate (PR) was studied in a sample of 1,242 Jerusalem youngsters and 1,703 adults. Confounding effects of age, body mass, ethnic origin and season were controlled in the analysis. Both mean systolic (SBP) and diastolic blood pressure (DBP) were lower in smokers than in nonsmokers, with greater differences in both generations in females (women 4.5 mm Hg, P = 0.004 and girls 3.9 mm Hg, P less than 0.001 for SBP; women 2.3 mm Hg, P = 0.024 and girls 2.6 mm Hg, P = 0.002 for DBP) than among the males (men 1.5 mm Hg, P = 0.15 and boys 2.0 mm Hg, P = 0.022 for SBP; men 1.3 mm Hg, P = 0.05 and boys 1.8 mm Hg, P = 0.01 for DBP). The relative odds of being in the upper age, ethnic and body mass index-adjusted quintiles of SBP for nonsmokers were 1.3, 1.9, 2.1, and 3.5 for men, boys, women, and girls, respectively. For DBP they were 1.3, 1.7, 1.1, and 2.1, respectively. No significant trends for BP varying with number of cigarettes smoked were noted in either adults or youngsters. Only adult male smokers had slightly higher PRs. The relatively small differences in BP may be of pharmacologic or psychobehavioral interest, but do not counter the well-described deleterious effects of cigarette smoking.     

Community consultation in socially sensitive research: Lessons from clinical trials of treatments for AIDS.

Contends that few studies have more starkly posed the dilemmas in socially sensitive research than the recent and ongoing clinical trials of medications (such as azidothymidine [AZT]) to treat acquired immune deficiency syndrome (AIDS). One response to such dilemmas is to include potential participants or surrogates for them in decision making. Although the investigator and relevant regulatory bodies are not absolved of responsibility by community consultation, such a procedure may help to create a partnership between the investigator and participants, consistent with ethical duties of respect for persons, beneficence, and fidelity. Community consultation also may dampen participants' anxiety and increase perceived justice of decisions about the research. Such a procedure has the potential to mitigate ethical problems in research involving a wide variety of socially sensitive topics and in randomized clinical trials of treatments for conditions other than AIDS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prevalence, incidence, and risks for HIV-1 infection in female sex workers in Miami, Florida

Annual cross-sectional prevalence, incidence of new infection, and risks for human immunodeficiency virus type 1 (HIV-1) infection were studied in 607 women convicted of prostitution between October 1987 and December 1990 and tested for HIV under court order. Cross-sectional prevalence was stable for 4 years (23-24% positivity in 1987-1991, p = 0.6). However, the incidence of new infections (rate of seroconversion) in 264 women tested more than once increased significantly each year from 12 per 100 person-years in 1987-1988 to 19 per 100 person-years in 1991 (p < 0.03). Seroconverters were more likely to be young black women with a prior history of syphilis or gonorrhea. A new episode of syphilis or rectal gonorrhea during the follow-up period predicted HIV seroconversion in a survival analysis model. Female sex workers are at great risk of acquiring HIV infection. Although HIV prevalence in cross-sectional samples was stable, incidence was increasing. Interpretation of prevalence trends from convenience samples, such as screening programs, may be difficult because changes in incidence may not be detected.     

Herpes zoster, immunological deterioration and disease progression in HIV-1 infection

OBJECTIVE: To study the incidence of herpes zoster, the relationship between herpes zoster and immunological markers, and the prognostic value of herpes zoster for progression of HIV disease. DESIGN AND METHODS: A total of 966 homosexual participants in The Amsterdam Cohort Study were studied. Herpes zoster was defined by its characteristic clinical presentation. Incidence was calculated using Poisson regression, cumulative incidence by the Kaplan-Meier product-limit method and the prognostic value was evaluated using Cox proportional hazards model. RESULTS: The incidence of first episodes of herpes zoster was 3.31 per 1000 person-years (PY) in HIV-seronegatives and 51.51 per 1000 PY in HIV-1-seropositive individuals. Recurrences only occurred in HIV-1-positive patients (25.6%). Cumulative incidences of first episodes increased linearly with the duration of follow-up. In HIV-1-seropositives the incidence was 31.2 per 1000 PY at CD4+ cells > or = 500 x 10(6)/l, 47.2 per 1000 PY [relative risk (RR), 1.51; 95% confidence interval (CI), 0.78-2.94] at CD4+ cells 200-499 x 10(6)/l and 97.5 per 1000 PY (RR, 3.13; 95% CI, 1.54-6.32) at CD4+ cells < 200 x 10(6)/l. Besides CD4+ cell counts, CD3 monoclonal antibodies and phytohaemagglutinin-induced T-cell reactivity were independent predictors for herpes zoster. The hazard ratio for AIDS after herpes zoster was 1.6 (95% CI, 1.1-2.4) and for death 1.7 (95% CI, 1.1-2.5), but these were not independent from CD4+ cell counts. CONCLUSION: In HIV-1 infection the incidence of herpes zoster increases with the decrease of CD4+ cell counts and T-cell reactivity, but herpes zoster is not an independent predictor for disease progression.