Demographic and HIV-specific characteristics of participants enrolled in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: The risks and benefits of initiating antiretroviral treatment (ART) at high CD4 cell counts have not been reliably quantified. The Strategic Timing of AntiRetroviral Treatment (START) study is a randomized international clinical trial that compares immediate with deferred initiation of ART for HIV-positive individuals with CD4 cell counts above 500 cells/µL. We describe the demographics, HIV-specific characteristics and medical history of this cohort. METHODS: Data collected at baseline include demographics, HIV-specific laboratory values, prior medical diagnoses and concomitant medications. Baseline characteristics were compared by geographical region, gender and age. RESULTS: START enrolled 4685 HIV-positive participants from 215 sites in 35 countries. The median age is 36 years [interquartile range (IQR) 29-44 years], 27% are female, and 45% self-identify as white, 30% as black, 14% as Latino/Hispanic, 8% as Asian and 3% as other. The route of HIV acquisition is reported as men who have sex with men in 55% of participants, heterosexual sex in 38%, injecting drug use in 1% and other/unknown in 5%. Median time since HIV diagnosis is 1.0 year (IQR 0.4-3.0 years) and the median CD4 cell count and HIV RNA values at study entry are 651 cells/µL (IQR 584-765 cells/µL) and 12,754 HIV RNA copies/mL (IQR 3014-43,607 copies/mL), respectively. CONCLUSIONS: START has enrolled a diverse group of ART-naïve individuals with high CD4 cell counts who are comparable to the HIV-positive population from the regions in which they were enrolled. The information collected with this robust study design will provide a database with which to evaluate the risks and benefits of early ART use for many important outcomes.

Interleukin-2 therapy in patients with HIV infection.

BACKGROUND: Used in combination with antiretroviral therapy, subcutaneous recombinant interleukin-2 raises CD4+ cell counts more than does antiretroviral therapy alone. The clinical implication of these increases is not known. METHODS: We conducted two trials: the Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy (SILCAAT) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). In each, patients infected with the human immunodeficiency virus (HIV) who had CD4+ cell counts of either 50 to 299 per cubic millimeter (SILCAAT) or 300 or more per cubic millimeter (ESPRIT) were randomly assigned to receive interleukin-2 plus antiretroviral therapy or antiretroviral therapy alone. The interleukin-2 regimen consisted of cycles of 5 consecutive days each, administered at 8-week intervals. The SILCAAT study involved six cycles and a dose of 4.5 million IU of interleukin-2 twice daily; ESPRIT involved three cycles and a dose of 7.5 million IU twice daily. Additional cycles were recommended to maintain the CD4+ cell count above predefined target levels. The primary end point of both studies was opportunistic disease or death from any cause. RESULTS: In the SILCAAT study, 1695 patients (849 receiving interleukin-2 plus antiretroviral therapy and 846 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 202 cells per cubic millimeter were enrolled; in ESPRIT, 4111 patients (2071 receiving interleukin-2 plus antiretroviral therapy and 2040 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 457 cells per cubic millimeter were enrolled. Over a median follow-up period of 7 to 8 years, the CD4+ cell count was higher in the interleukin-2 group than in the group receiving antiretroviral therapy alone--by 53 and 159 cells per cubic millimeter, on average, in the SILCAAT study and ESPRIT, respectively. Hazard ratios for opportunistic disease or death from any cause with interleukin-2 plus antiretroviral therapy (vs. antiretroviral therapy alone) were 0.91 (95% confidence interval [CI], 0.70 to 1.18; P=0.47) in the SILCAAT study and 0.94 (95% CI, 0.75 to 1.16; P=0.55) in ESPRIT. The hazard ratios for death from any cause and for grade 4 clinical events were 1.06 (P=0.73) and 1.10 (P=0.35), respectively, in the SILCAAT study and 0.90 (P=0.42) and 1.23 (P=0.003), respectively, in ESPRIT. CONCLUSIONS: Despite a substantial and sustained increase in the CD4+ cell count, as compared with antiretroviral therapy alone, interleukin-2 plus antiretroviral therapy yielded no clinical benefit in either study. (ClinicalTrials.gov numbers, NCT00004978 [ESPRIT] and NCT00013611 [SILCAAT study].)

Predictors of bacterial pneumonia in Evaluation of Subcutaneous Interleukin-2 in a Randomized International Trial (ESPRIT).

BACKGROUND AND OBJECTIVES: Bacterial pneumonia still contributes to morbidity/mortality in HIV infection despite effective combination antiretroviral therapy (cART). Evaluation of Subcutaneous Interleukin-2 in a Randomized International Trial (ESPRIT), a trial of intermittent recombinant interleukin-2 (rIL-2) with cART vs. cART alone (control arm) in HIV-infected adults with CD4 counts ≥300cells/µL, offered the opportunity to explore associations between bacterial pneumonia and rIL-2, a cytokine that increases the risk of some bacterial infections. METHODS: Baseline and time-updated factors associated with first-episode pneumonia on study were analysed using multivariate proportional hazards regression models. Information on smoking/pneumococcal vaccination history was not collected. RESULTS: IL-2 cycling was most intense in years 1-2. Over ≈7 years, 93 IL-2 [rate 0.67/100 person-years (PY)] and 86 control (rate 0.63/100 PY) patients experienced a pneumonia event [hazard ratio (HR) 1.06; 95% confidence interval (CI) 0.79, 1.42; P=0.68]. Median CD4 counts prior to pneumonia were 570cells/µL (IL-2 arm) and 463cells/µL (control arm). Baseline risks for bacterial pneumonia included older age, injecting drug use, detectable HIV viral load (VL) and previous recurrent pneumonia; Asian ethnicity was associated with decreased risk. Higher proximal VL (HR for 1 log(10) higher VL 1.28; 95% CI 1.11, 1.47; P<0.001) was associated with increased risk; higher CD4 count prior to the event (HR per 100 cells/µL higher 0.94; 95% CI 0.89, 1.0; P=0.04) decreased risk. Compared with controls, the hazard for a pneumonia event was higher if rIL-2 was received <180 days previously (HR 1.66; 95% CI 1.07, 2.60; P=0.02) vs.≥180 days previously (HR 0.98; 95% CI 0.70, 1.37; P=0.9). Compared with the control group, pneumonia risk in the IL-2 arm decreased over time, with HRs of 1.41, 1.71, 1.16, 0.62 and 0.84 in years 1, 2, 3-4, 5-6 and 7, respectively. CONCLUSIONS: Bacterial pneumonia rates in cART-treated adults with moderate immunodeficiency are high. The mechanism of the association between bacterial pneumonia and recent IL-2 receipt and/or detectable HIV viraemia warrants further exploration.

CD4+ count-guided interruption of antiretroviral treatment.

BACKGROUND: Despite declines in morbidity and mortality with the use of combination antiretroviral therapy, its effectiveness is limited by adverse events, problems with adherence, and resistance of the human immunodeficiency virus (HIV). METHODS: We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease. RESULTS: A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1 to 2.5; P=0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1). CONCLUSIONS: Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy. (ClinicalTrials.gov number, NCT00027352 [ClinicalTrials.gov].).

Spontaneous pneumothorax with Pneumocystis carinii infection. Occurrence in patients with acquired immunodeficiency syndrome.

Two patients with acquired immunodeficiency syndrome developed spontaneous pneumothorax during the course of Pneumocystis carinii pneumonia. The pneumothorax in each of these patients was a primary event, unrelated to biopsy or mechanical ventilation. To our knowledge, this complication of P carinii infection has not been noted in adults before and is an important consideration for those caring for persons with this illness.

Delayed diagnosis of pulmonary tuberculosis in city hospitals.

BACKGROUND: Delays in the diagnosis of tuberculosis may result in increased patient morbidity and in further spread of the disease. We examined the clinical acumen of the medical staff in the diagnosis of tuberculosis and investigated the reasons for delay in the identification and treatment of patients with pulmonary tuberculosis. METHODS: A retrospective chart review was undertaken between July 1985 and June 1988 on all patients with culture-proven pulmonary tuberculosis at two inner city hospitals. Time intervals between admission and the clinical suspicion, diagnosis, and treatment of tuberculosis were determined. Clinical features were evaluated for their effect on these time intervals. RESULTS: Eighty-five patients with culture-proven pulmonary tuberculosis were identified. Tuberculosis was suspected in 36 patients on admission. By the end of 1 week, tuberculosis was confirmed in 50 patients and suspected in 23 others. Twenty percent of patients either died or were discharged before the diagnosis of tuberculosis was made. Older patients (> 65 years) were misdiagnosed more commonly than younger patients (82% vs 48%). Patients without respiratory symptoms were misdiagnosed more frequently (78% vs 49%) than were those with symptoms. Other reasons for delayed diagnosis and treatment included low use of tuberculin skin tests, misinterpretation of unusual chest roentgenograms, and waiting for culture results in patients with negative acid-fast smears. CONCLUSIONS: The diagnosis and treatment of patients with pulmonary tuberculosis is often delayed owing to atypical presentations and slow confirmation by culture. Improved clinical acumen, development of rapid diagnostic tests, and the institution of early empiric therapy are desirable to control this disease.

Knowledge of AIDS among hospital workers: behavioral correlates and consequences.

Incidents of suboptimal care being rendered to AIDS patients have been documented. Using a voluntary anonymous questionnaire, we surveyed the employees of a large urban hospital in order to evaluate the knowledge, attitudes and professional behavior of the staff regarding AIDS. Responses were obtained from 1194 (60%) of the staff. Poor knowledge of the transmission of AIDS was documented, with 50% of workers stating that AIDS can be spread through ordinary non-sexual contact and 23% through the air by a cough or a sneeze. One-third of employees believed that they should be able to refuse to care for patients with AIDS. Extreme anxiety in dealing with AIDS patients was noted by 25% of employees, and only 16% of the employees would volunteer to work on an AIDS ward. Knowledge regarding AIDS was demonstrated to be a predictor of positive attitudes, appropriate professional behavior and lower anxiety in dealing with AIDS patients. The goal of hospital education programs on AIDS must be to ensure the incorporation of accurate information into the belief system of workers.

Cigarette smoking: a modifier of human immunodeficiency virus type 1 infection?

Two hundred and two homosexual men enrolled in a prospective cohort study of AIDS risk were assessed for differences in the occurrence and progression of human immunodeficiency virus type 1 (HIV-1) infection with respect to cigarette smoking. Among subjects who were initially seronegative, smokers were more likely than nonsmokers to become HIV-1 seropositive (p = 0.03). After seroconversion, serum beta 2-microglobulin and CD4+ lymphocyte levels were elevated in cigarette smokers relative to nonsmokers (p = 0.02 for both comparisons), but both of these differences disappeared within 2 years. There was no detectable difference in the risk of AIDS or Pneumocystis carinii pneumonia with respect to smoking. Our data suggest that cigarette smoking may alter the immune response to HIV-1 infection, but it appears to have no marked effect on clinical outcome. They also suggest that cigarette smoking may be a surrogate marker for continued high-risk sexual behavior in homosexual men.

Amdinocillin therapy of experimental animal infections.

Amdinocillin has been shown to have broad coverage in vitro against many strains of Enterobacteriaceae. Synergy has been demonstrated in vitro with several other beta-lactam antibiotics. The rabbit model of meningitis was used to study the in vivo effectiveness of amdinocillin when combined with other beta-lactams for serious infections. Organisms that showed an enhanced in vitro bactericidal effect from the combination of amdinocillin and another beta-lactam showed more rapid elimination of the organisms in vivo.

Aerosol pentamidine prophylaxis following Pneumocystis carinii pneumonia in AIDS patients: results of a blinded dose-comparison study using an ultrasonic nebulizer.

PURPOSE: To compare the efficacy and safety of three different doses of prophylactic aerosol pentamidine in patients with one prior episode of Pneumocystis carinii pneumonia (PCP) and the acquired immunodeficiency syndrome. PATIENTS AND METHODS: The design of the study was a double-blind, randomized, dose-comparison clinical trial conducted at 13 medical centers within the United States. In stage I of the trial, patients were randomized to receive either 5 mg, 60 mg, or 120 mg of aerosol pentamidine delivered biweekly with the Fisoneb (Fisons, Inc., Rochester, New York) ultrasonic nebulizer. After 24 weeks of therapy, patients entered stage II of the trial, where the 5-mg group was re-randomized to either the 60-mg or 120-mg group. RESULTS: One hundred seventy-five patients entered stage I of the trial and received prophylaxis for a mean of 123.6 days. Seven assigned to the 5-mg biweekly dosing schedule had a confirmed recurrence of PCP, compared with none in the 60-mg group (p = 0.007) and three in the 120-mg group (p = 0.304). During stage II of the trial, eight patients in the 60-mg group and one additional patient in the 120-mg group had recurrent PCP. After 52 weeks of observation, the likelihood of being PCP-free was 88.0% in the 60-mg group and 93% in the 120-mg group (p = 0.712). Minor adverse events related to aerosol pentamidine administration included cough, taste perversion, chest pain, bronchospasm, and dyspnea. These side effects were more common in the 60-mg and 120-mg treatment groups and resulted in withdrawal from the study by one patient. Serious events were more common after 24 weeks of therapy and included asymptomatic hypoglycemia (five), pancreatitis (two), pneumothorax (one), and extrapulmonary pneumocystosis (one). CONCLUSIONS: These results demonstrate that biweekly administration of 60 mg or 120 mg of aerosol pentamidine significantly decreases PCP recurrence when compared with a 5-mg regimen or findings in historic controls and is generally well tolerated. There is no significant difference in effect or safety between these two dosing regimens in patients followed for at least 52 weeks of therapy.

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.

Nontuberculous mycobacterial infections.

The acquired immunodeficiency syndrome (AIDS) pandemic has led to greater understanding and respect for the pathogenic potential of non-tuberculous mycobacteria. Mycobacterium avium complex (MAC) has emerged as the most common systemic bacterial infection in AIDS, causing debilitating disseminated disease in late-stage HIV-infected patients. With the release of the macrolide antibiotics, clarithromycin and azithromycin, effective and well-tolerated therapeutic regimens for MAC have been developed which prolong survival and increase quality of life. The macrolides and rifabutin are also effective as preventive therapy for MAC in patients with AIDS. Mycobacterium kansasii, which causes pulmonary disease similar to tuberculosis as well as disseminated disease in AIDS, is treatable with isoniazid, rifampin and ethambutol. Clinical syndromes and therapeutic options for other non-tuberculous mycobacteria in AIDS are also reviewed.

Mycobacterium szulgai infection of the lung: case report and review of an unusual pathogen.

The nontuberculous mycobacteria are responsible for considerable morbidity in the immunocompromised and immunocompetent host, especially in the older patient with chronic fibrotic or cavitary disease of the lung. Mycobacterium szulgai is a slow growing mycobacterium infrequent in nature and man. Except from a snail and a tropical fish, it has been isolated only from humans and nearly always represents a true pathogen. Three-drug therapy using in vitro susceptibilities as a guide for 12 to 18 months increases the likelihood of success. We present a patient who developed M szulgai pulmonary infection 30 years after an episode of pulmonary tuberculosis. After successful therapy for his M szulgai infection, this patient developed chronic pulmonary histoplasmosis. We review the 25 years of clinical experience with this mycobacteria; particular emphasis is on the presentation and treatment of this very unusual infection.

Geographic and seasonal variation in Mycobacterium avium bacteremia among North American patients with AIDS.

Analysis of geographic risk was performed for Mycobacterium avium complex (MAC) bacteremia among North American patients with AIDS. Monthly mycobacterial blood cultures were taken from patients who were placebo recipients in a prospective evaluation of MAC prophylaxis. Of 571 patients, 102 (17.9%) acquired MAC bacteremia during an average follow-up of 256 days. The area with the highest risk for MAC was the South Central region (27.9%; P < 0.02), whereas the area with the lowest risk was Canada (11.3%; P = 0.12). When the southern states were combined and compared with the northern states and Canada, the incidence of MAC bacteremia was higher in the southern states (21.6% versus 14.0%, P < 0.03). Proportional hazards analysis was performed for the difference between the North and South and controlled for baseline CD4 cell count. In this analysis, time to MAC was significantly longer in the North (hazard ratio = 0.587, 95% confidence interval 0.390 to 0.883, P = 0.01). Although overall variation in seasonality was not marked, there was a significant decrease in cases in the North during the summer months (P < 0.01). We conclude that geographic location is a risk factor for MAC bacteremia in patients with advanced AIDS, with decreased risk in northern North America.

The validity of acid-fast smears in the diagnosis of pulmonary tuberculosis.

The acid-fast smear remains an important tool in the diagnosis of tuberculosis. Some reports have questioned the validity of this stain in situations of low prevalence. We examined the relationship between prevalence and predictive value of sputum smears in one laboratory during periods of both low and high laboratory prevalence of Mycobacterium tuberculosis. Smears were examined by fluorescence and confirmed by Kinyoun stain. The number of samples positive for mycobacteria increased from 128 (4.3%) of 2956 during the 1975 through 1978 study period to 197 (8.4%) of 2347 during the 1979 through 1982 study period. Of 47 positive smears during the first study period, only one was a false-positive. None of 96 positive smears during the second period was a false-positive. The positive predictive value of acid-fast microscopy was 97.9% and 100% for the two periods examined. We have demonstrated in practice the small effect of a shift in prevalence on the positive predictive value of an acid-fast smear when specificity is maintained.

A large-scale, rapid public health response to rabies in an organ recipient and the previously undiagnosed organ donor.

This article describes and contrasts the public health response to two human rabies cases: one organ recipient diagnosed within days of symptom onset and the transplant donor who was diagnosed 18 months post-symptom onset. In response to an organ-transplant-related rabies case diagnosed in 2013, organ donor and recipient investigations were conducted by multiple public health agencies. Persons with potential exposure to infectious patient materials were assessed for rabies virus exposure. An exposure investigation was conducted to determine the source of the organ donor's infection. Over 100 persons from more than 20 agencies spent over 2700 h conducting contact investigations in healthcare, military and community settings. The 564 persons assessed include 417 healthcare workers [5.8% recommended for post-exposure prophylaxis (PEP)], 96 community contacts (15.6% recommended for PEP), 30 autopsy personnel (50% recommended for PEP), and 21 other persons (4.8% recommended for PEP). Donor contacts represented 188 assessed with 20.2% recommended for PEP, compared with 5.6% of 306 recipient contacts recommended for PEP. Human rabies cases result in substantial use of public health and medical resources, especially when diagnosis is delayed. Although rare, clinicians should consider rabies in cases of encephalitis of unexplained aetiology, particularly for cases that may result in organ donation.

Prophylaxis of Mycobacterium avium complex bacteremia in patients with AIDS.

Prevention of opportunistic infections is an integral part of caring for patients infected with human immunodeficiency virus. Mycobacterium avium complex (MAC) bacteremia can cause severe morbidity and excess mortality among these patients. Controlled trials of rifabutin for the prophylaxis of MAC bacteremia have been completed. Rifabutin reduced the incidence of MAC bacteremia by approximately one-half and, when disseminated disease due to MAC (DMAC) did develop, reduced the frequency of associated clinical symptoms. Moreover, prophylaxis with rifabutin was well tolerated. Prophylaxis of MAC bacteremia with macrolide antibiotics is currently being investigated, but no data from large-scale prospective trials are yet available. On the basis of trials completed thus far, the U.S. Public Health Service has recently recommended the use of rifabutin (300 mg/d) as prophylaxis for MAC bacteremia in patients with fewer than 100 CD4+ lymphocytes/mm3. The widespread use of this prophylactic regimen could reduce the rates of morbidity and mortality caused by DMAC. However, rifabutin must be administered only after careful consideration of the circumstances of individual patients. Potential drug interactions, cost, and compliance are important factors in the decision about which patients should receive prophylaxis.