Fred R. Sattler

A Controlled Trial of Early Adjunctive Treatment with Corticosteroids for Pneumocystis carinii Pneumonia in the Acquired Immunodeficiency Syndrome

BACKGROUND Pneumocystis carinii pneumonia remains a common cause of serious morbidity and mortality in patients with the acquired immunodeficiency syndrome (AIDS). The extensive lung injury that accompanies pneumocystis-associated respiratory failure and the reports of clinical benefit from the use of adjunctive corticosteroids provided the rationale for this prospective multicenter trial. METHODS A total of 333 patients with AIDS and pneumocystis pneumonia received standard treatment and were randomly assigned to receive either corticosteroids (beginning with the equivalent of 40 mg of prednisone twice daily) or no additional therapy. The primary end points in this unblinded trial were the occurrence of respiratory failure (hypoxemia ratio [partial pressure of arterial oxygen divided by fraction of inspired oxygen] less than 75, intubation, or death), death, and dose-limiting toxicity of the initial standard therapy. RESULTS Of the patients with confirmed or presumed pneumocystis pneumonia (n = 225 and n = 26, respectively), those assigned to treatment with corticosteroids had a lower cumulative risk at 31 days of respiratory failure (0.14 vs. 0.30, P = 0.004) and of death (0.11 vs. 0.23, P = 0.009), as well as a lower risk of death within 84 days (0.16 vs. 0.26, P = 0.026). The frequency of dose-limiting toxicity of the standard therapy was similar in the two treatment groups. Intention-to-treat analyses of the entire cohort confirmed these findings. Clinical benefit could not be demonstrated, however, for patients with mild disease (hypoxemia ratio, greater than 350), equivalent to a partial pressure of oxygen greater than 75 torr on room air. The patients assigned to corticosteroid treatment had an excess of localized herpetic lesions (26 percent vs. 15 percent, P = 0.04) but not of other infections or of neoplasms. CONCLUSIONS Early adjunctive treatment with corticosteroids reduces the risks of respiratory failure and death in patients with AIDS and moderate-to-severe pneumocystis pneumonia. Because the adverse effects are few, corticosteroids should be included as part of the initial treatment for persons with AIDS who have moderate-to-severe pneumocystis pneumonia.

Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy

Summary Background In previous natural history studies and clinical trials, AIDS-related cytomegalovirus (CMV) retinitis has occurred primarily in patients with absolute CD4 counts of 50 cells/μL or less (0·05×10 9 /L) at the time of diagnosis. Methods We report five patients identified from our clinical practices who were diagnosed with CMV retinitis while their CD4 counts were above 195 cells/μL. We also analysed, based on CD4 counts, 76 AIDS patients with newly diagnosed CMV retinitis whose CD4 lymphocyte enumerations were done in laboratories that maintained certification in a common external quality control programme. Findings 5–24 weeks before retinitis was diagnosed, all five patients had had absolute CD4 lymphocyte counts of less than 85 cells/μL, and 4–7 weeks before diagnosis, all five patients had started taking highly active antiretroviral treatment (HAART) regimens. Only one (4%) of 27 patients enrolled in the trial between July, 1995, and February, 1996, had an absolute CD4 count of more than 50 cells/μL, and none of 27 had an absolute CD4 count of more than 100/μL on entry to the trial. However, from March, 1996 (when indinavir and ritonavir were approved by the FDA for marketing in the USA), to August, 1996, 14 (29%) of 49 patients had CD4 counts of more than 50/μL and seven (14%) of 49 had a CD4 count of more than 100 cells/μL on entry. Interpretation These findings suggest that the early immunological effects of HAART may not provide sufficient protection to prevent CMV retinitis in patients who have very low CD4 counts when therapy is started. Clinicians should note that CMV retinitis may now occur in patients who have CD4 counts of more than 100 cells/μL.

Prophylaxis against Disseminated Mycobacterium avium Complex with Weekly Azithromycin, Daily Rifabutin, or Both

BACKGROUND Azithromycin is active in treating Mycobacterium avium complex disease, but it has not been evaluated as primary prophylaxis in patients with human immunodeficiency virus (HIV) infection. Because the drug is concentrated in macrophages and has a long half-life in tissue, there is a rationale for once-weekly dosing. METHODS We compared three prophylactic regimens in a multicenter, double-blind, randomized trial involving 693 HIV-infected patients with fewer than 100 CD4 cells per cubic millimeter. The patients were assigned to receive rifabutin (300 mg daily), azithromycin (1200 mg weekly), or both drugs. They were monitored monthly with blood cultures for M. avium complex. RESULTS In an intention-to-treat analysis, the incidence of disseminated M. avium complex infection at one year was 15.3 percent with rifabutin, 7.6 percent with azithromycin, and 2.8 percent with both drugs. The risk of the infection in the azithromycin group was half that in the rifabutin group (hazard ratio, 0.53; P = 0.008). The risk was even lower when two-drug prophylaxis was compared with rifabutin alone (hazard ratio, 0.28; P<0.001) or azithromycin alone (hazard ratio, 0.53; P = 0.03). Among the patients in whom azithromycin prophylaxis was not successful, 11 percent of M. avium complex isolates were resistant to azithromycin. Dose-limiting toxic effects were more common with the two-drug combination than with azithromycin alone (hazard ratio, 1.67; P=0.03). Survival was similar in all three groups. CONCLUSIONS For protection against disseminated M. avium complex infection, once-weekly azithromycin is more effective than daily rifabutin and infrequently selects for resistant isolates. Rifabutin plus azithromycin is even more effective but is not as well tolerated.

Trimethoprim-Sulfamethoxazole Compared with Pentamidine for Treatment of Pneumocystis carinii Pneumonia in the Acquired Immunodeficiency Syndrome: A Prospective, Noncrossover Study

STUDY OBJECTIVE To ascertain the efficacy and toxicity of trimethoprim-sulfamethoxazole or pentamidine when either is given alone during the entire treatment period for Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN Prospective, randomized, noncrossover comparison of trimethoprim-sulfamethoxazole with pentamidine. Trimethoprim-sulfamethoxazole dosage was adjusted to maintain serum trimethoprim at 5 to 8 micrograms/mL. Pentamidine dosage was reduced by 30% to 50% for an absolute rise in serum creatinine of more than 88 mumol/L (1 mg/dL). SETTING Tertiary care hospital and AIDS clinic. PATIENTS Thirty-six patients were treated with trimethoprim-sulfamethoxazole and 34 with pentamidine. Pretreatment clinical features and laboratory test results were similar in the two groups. MEASUREMENTS AND MAIN RESULTS Thirty-six recipients of trimethoprim-sulfamethoxazole and 33 recipients of pentamidine completed therapy without crossover. Trimethoprim-sulfamethoxazole caused a rash (44%) and anemia (39%) more frequently (P less than or equal to 0.03, whereas pentamidine caused nephrotoxicity (64%), hypotension (27%), or hypoglycemia (21%) more frequently (P less than or equal to 0.01). The (A - a)DO2 improved by greater than 1.3 kPa (10 mmHg) 8 days earlier for trimethoprim-sulfamethoxazole recipients (95% CI for the difference in response, -1 to 17; P = 0.04). Thirty-one (86%) patients treated with trimethoprim-sulfamethoxazole and 20 (61%) with pentamidine survived and were without respiratory support at completion of treatment (95% CI for the difference in response, 5% to 45%; P = 0.03). CONCLUSIONS For most patients with AIDS and P. carinii pneumonia, successful treatment with a single agent is possible. Toxicity associated with the two standard treatments is rarely life-threatening and may be diminished if the trimethoprim-sulfamethoxazole dosage is modified by pharmacokinetic monitoring and the pentamidine dosage is reduced for nephrotoxicity. Oxygenation improved more quickly and survival was better with trimethoprim-sulfamethoxazole.

Clarithromycin Therapy for Bacteremic Mycobacterium avium Complex Disease: A Randomized, Double-Blind, Dose-Ranging Study in Patients with AIDS

Disseminated infections with Mycobacterium avium complex are increasingly common in advanced human immunodeficiency virus (HIV) disease and cause substantial morbidity [1, 2]. In persons with HIV infection and CD4 lymphocyte counts less than 100 cells/mm3, the probability of developing M. avium complex disease or bacteremia is 10% to 20% per year [3, 4]. Bacteremia involving M. avium complex produces a wide array of clinical signs and symptoms, including wasting, fever, and night sweats, and is associated with decreased survival [3, 5, 6]. Treatment of disseminated M. avium complex bacteremia with conventional antimycobacterial agents, such as isoniazid, rifampin or rifabutin, ethambutol, and clofazimine, has been disappointing. Relatively few patients respond clinically, and continuous bacteremia persists in most patients despite treatment [7-9]. Combination therapy with four to five agents, including amikacin and fluoroquinolones, has resulted in diminution of M. avium complex bacteremia and alleviation of symptoms in several small studies, although toxicity with combination regimens was substantial [10-13]. Recently, several new macrolide antibiotics have been identified that possess enhanced antimycobacterial activity in vitro [14]. Clarithromycin and azithromycin have been shown in pilot studies [15, 16] to decrease the quantity of M. avium complex organisms in the blood of patients with the acquired immunodeficiency syndrome (AIDS) who were treated with these agents for short periods of time. To further characterize the activity of clarithromycin as a single agent in the treatment of disseminated M. avium complex disease in patients with HIV infection, we did a randomized, double-blind study of three different doses of clarithromycin monotherapy. Because the optimal duration of therapy for M. avium complex disease in patients with AIDS was not known and because the emergence of drug-resistant organisms was of concern, our study was limited to 12 weeks. Patients having a clinical and bacteriologic response at the completion of study were permitted to extend their therapy for up to 1 year with the option of adding other antimycobacterial agents. Methods Patients Patients were eligible for enrollment if they had HIV infection and a blood culture that grew M. avium complex within 60 days before entry. Patients could not have received any antimycobacterial agents for at least 4 weeks before entry into the study; those with a history of severe allergic reactions to erythromycin were excluded. Patients were enrolled at six centers, three within the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group (ACTG) and three sites funded by Abbott Laboratories. Written informed consent was obtained from all study participants. Enrollment began 1 May 1991 and was completed by 30 November 1991. Patients were randomly assigned to treatment with one of three doses of clarithromycin (Biaxin, Abbott Laboratories, North Chicago, Illinois): 500 mg twice daily, 1000 mg twice daily, or 2000 mg twice daily. Neither patients nor study staff were aware of the dose group to which patients were assigned. Randomization was done in blocks of six and was stratified by site of enrollment. Because the safety of 2000 mg of clarithromycin twice daily in patients with HIV infection was not established when the study began, the first group of 36 patients were randomly assigned to receive 500 mg or 1000 mg twice daily. A 2:1 randomization scheme was used, with two patients assigned to the 500-mg group for each patient assigned to the 1000-mg group. After the start of the study, the safety of 2000 mg of clarithromycin twice daily was shown in a phase 1 trial [17], and the second group of 36 patients were randomly assigned in a 2:1 manner to receive clarithromycin at 2000 mg or 1000 mg twice daily. Thus, after the first 72 patients were enrolled, 24 had been randomly assigned to each dose group. The remainder of the patients were randomly assigned 1:1:1 to the three dose groups. For each dose, patients took four capsulesof which one, two, or four were clarithromycin at 500 mgand the remainder were identical-appearing placebos. Patients were evaluated weekly for 2 weeks, then biweekly through week 12. At each study visit, an interval history was taken, a targeted physical examination was done, and blood was collected for culture and other monitoring tests. After 12 weeks of therapy, patients having a clinical or bacteriologic response were permitted to extend their therapy for up to 1 year, with the option to add other antimycobacterial agents at the discretion of the investigator. Mycobacteriologic Analyses Quantitative blood cultures for mycobacteria were done twice before initiating study therapy and every 2 weeks for the 12 weeks of the study. Cultures were done in the Mycobacteriology Clinical Reference Laboratory at the National Jewish Center for Immunology and Respiratory Medicine in Denver, Colorado, by methods previously reported [18]. In brief, 5 to 8 mL of blood was obtained in previously labeled vacutainer tubes containing 1.7 mL of sodium polyanetholsulfate solution as an anticoagulant. Specimens were shipped at ambient temperature by overnight mail to Denver; shipping of mycobacterial cultures in this manner does not affect viability or quantitative results [19]. After receipt in the laboratory, cultures were mixed with 20 mL of a lysing solution that contained 0.45% sodium deoxycholate and 0.09% sodium polyanetholsulfate. After manual mixing, tubes were centrifuged at 3500 g for 30 minutes in a refrigerated centrifuge, and the supernatant was decanted. The pellet was resuspended, and 0.2% bovine albumin was added to yield a final volume of 2.5 mL. The suspension was inoculated onto two 7H11 agar plates, with 0.5 mL distributed on each plate. A third 7H11 agar plate was inoculated with 0.5 mL of the suspension diluted to 1:100. The plates were then incubated at 37 C in the presence of 5% CO2. The remaining 1.0 mL of suspension was inoculated into liquid 7H12 medium in a BACTEC vial (Becton Dickinson Diagnostic Instrument Systems, Sparks, Maryland), which was incubated at 37 C. Growth in the BACTEC vial was monitored radiometrically daily, and results were reported as positive if the growth index was more than 20. Cultures were considered negative if no growth was observed within 2 weeks in BACTEC. All culture-positive vials were incubated until the growth index was more than 500 to permit speciation and drug susceptibility testing. Speciation was done using hybridized DNA-RNA probes for M. avium and M. intracellulare (AccuProbe, Gen-Probe, San Diego, California). Quantitative colony counts were determined by counting the number of colonies of mycobacteria on the agar plates, followed by a calculation that took into account the concentration coefficient and the initial volume of each blood specimen. If colonies were too numerous to count on duplicate plates, colonies on the plate inoculated with a diluted 1:100 sample were counted. Susceptibility testing of isolates to clarithromycin was done in 7H12 broth at pH 7.4 by the dilution method of Heifets as previously described [18, 20]. Because peak serum concentrations of clarithromycin are 4 to 10 g/mL with drug doses used in this study, we selected a minimal inhibitory concentration of 4 g/mL as the cut-point for susceptibility and selected more than 32 g/mL as the cut-point for resistance. Statistical Analyses Analyses were done to compare baseline characteristics among groups and to compare treatment outcomes within and among groups. Differences in categorical variables were assessed with the continuity-corrected chi-square test. Normally distributed continuous variables within groups were compared with the paired t-test, and skewed variables were compared with the Wilcoxon rank-sum test. Initial analyses were on an intent-to-treat basis, and all randomly assigned patients were included in safety and survival analyses. Bacteriologic analyses were done on all patients with a positive baseline culture and at least one follow-up culture. Median values for colony-forming units (CFUs) of M. avium complex/mL of blood at baseline were compared with follow-up values within and among groups using the Kruskal-Wallis test for three groups. The time to achieve cultures that were negative for M. avium complex (sterilization) in blood was estimated using the product-limit method, with differences assessed by the log-rank test. Survival was also estimated by the product-limit method. To assess the effect of baseline characteristics and treatment on survival, Cox proportional-hazards analysis was done. Results Between 1 May and 30 November 1991, 154 patients were enrolled in the study, 108 at the three ACTG sites and 46 at the other sites. Baseline characteristics of the study population are shown in Table 1. Baseline demographic characteristics were similar. Mean ages of patients in the three groups ranged from 34 to 38 years, and most patients were men. Thirty-one percent of patients enrolled were members of racial or ethnic minorities. Mean weights of participants were 60 to 62 kg. The mean baseline Karnofsky performance score was lower in patients assigned to 1000 mg of clarithromycin twice daily than in patients assigned to 500 mg or 2000 mg twice daily. The median time from diagnosis of M. avium complex infection to enrollment was 84 days for patients assigned to 500 mg twice daily, 64 days for patients assigned to 1000 mg twice daily, and 59 days for patients assigned to 2000 mg twice daily. Table 1. Baseline Demographic and Clinical Characteristics of Patients Treated with Clarithromycin* Baseline laboratory values of patients in the study are shown in Table 2. All patients were moderately anemic. Of note, serum lactate dehydrogenase and alkaline phosphatase levels were increased across all groups, with no statistical differences among groups. Patients were prof

Satellite cell numbers in young and older men 24 hours after eccentric exercise

We tested the hypothesis that the expansion of satellite cell numbers, 24 h after maximal eccentric knee extensor exercise, is blunted in older men. Muscle biopsies were obtained from the vastus lateralis of 10 young (23–35 years) and 9 older (60–75 years) men. Satellite cells were identified immunohistochemically using an antibody to neural cell adhesion molecule. After 92 maximal eccentric contractions, the mean number of satellite cells per muscle fiber increased to a greater extent among the young men (141%; P < 0.001) than older men (51%; P = 0.002) from preexercise levels. Similar results were obtained when satellite cells were expressed as a proportion of all sublaminar nuclei. We conclude that a single bout of maximal eccentric exercise increases satellite cell numbers in both age groups, with a significantly greater response among the young men. These data suggest that age‐related changes in satellite cell recruitment may contribute to muscle regeneration deficits among the elderly. Muscle Nerve 2006

Testosterone and Growth Hormone Improve Body Composition and Muscle Performance in Older Men

CONTEXT Impairments in the pituitary-gonadal axis with aging are associated with loss of muscle mass and function and accumulation of upper body fat. OBJECTIVES We tested the hypothesis that physiological supplementation with testosterone and GH together improves body composition and muscle performance in older men. DESIGN, SETTING, AND PARTICIPANTS One hundred twenty-two community-dwelling men 70.8 +/- 4.2 yr of age with body mass index of 27.4 +/- 3.4 kg/m2, testosterone of 550 ng/dl or less, and IGF-I in lower adult tertile (< or =167 ng/dl) were randomized to receive transdermal testosterone (5 or 10 g/d) during a Leydig cell clamp plus GH (0, 3, or 5 microg/kg . d) for 16 wk. MAIN OUTCOME MEASURES Body composition by dual-energy x-ray absorptiometry, muscle performance, and safety tests were conducted. RESULTS Total lean body mass increased (1.0 +/- 1.7 to 3.0 +/- 2.2 kg) as did appendicular lean tissue (0.4 +/- 1.4 to 1.5 +/- 1.3 kg), whereas total fat mass decreased by 0.4 +/- 0.9 to 2.3 +/- 1.7 kg as did trunk fat (0.5 +/- 0.9 to 1.5 +/- 1.0 kg) across the six treatment groups and by dose levels for each parameter (P < or = 0.0004 for linear trend). Composite maximum voluntary strength of upper and lower body muscles increased by 14 +/- 34 to 35 +/- 31% (P < 0.003 in the three highest dose groups) that correlated with changes in appendicular lean mass. Aerobic endurance increased in all six groups (average 96 +/- 137 sec longer). Systolic and diastolic blood pressure increased similarly in each group with mean increases of 12 +/- 14 and 8 +/- 8 mm Hg, respectively. Other predictable adverse events were modest and reversible. CONCLUSIONS Supplemental testosterone produced significant gains in total and appendicular lean mass, muscle strength, and aerobic endurance with significant reductions in whole-body and trunk fat. Outcomes appeared to be further enhanced with GH supplementation.

Aerobic Exercise Overcomes the Age-Related Insulin Resistance of Muscle Protein Metabolism by Improving Endothelial Function and Akt/Mammalian Target of Rapamycin Signaling

Muscle protein metabolism is resistant to insulins anabolic effect in healthy older subjects. This is associated with reduced insulin vasodilation. We hypothesized that aerobic exercise restores muscle protein anabolism in response to insulin by improving vasodilation in older subjects. We measured blood flow, endothelin-1, Akt/mammalian target of rapamycin (mTOR) signaling, and muscle protein kinetics in response to physiological local hyperinsulinemia in two groups of older subjects following a bout of aerobic exercise (EX group: aged 70 ± 2 years; 45-min treadmill walk, 70% heart rate max) or rest (CTRL group: aged 68 ± 1 years). Baseline endothelin-1 was lower and blood flow tended to be higher in the EX group, but protein kinetics was not different between groups. Insulin decreased endothelin-1 (P < 0.05) in both groups, but endothelin-1 remained higher in the CTRL group (P < 0.05) and blood flow increased only in the EX group (EX group: 3.8 ± 0.7 to 5.3 ± 0.8; CTRL group: 2.5 ± 0.2 to 2.6 ± 0.2 ml · min−1 · 100 ml leg−1). Insulin improved Akt phosphorylation in the EX group and increased mTOR/S6 kinase 1 phosphorylation and muscle protein synthesis (EX group: 49 ± 11 to 89 ± 23; CTRL group: 58 ± 8 to 57 ± 12 nmol · min−1 · 100 ml leg−1) in the EX group only (P < 0.05). Because breakdown did not change, net muscle protein balance became positive only in the EX group (P < 0.05). In conclusion, a bout of aerobic exercise restores the anabolic response of muscle proteins to insulin by improving endothelial function and Akt/mTOR signaling in older subjects.

Elevated blood pressure in subjects with lipodystrophy

ObjectivesTo assess the prevalence of elevated blood pressure in patients with lipodystrophy. DesignCase–control study. ParticipantsForty-two patients with abnormal body fat (100%) and serum lipids (86%) (HIV-positive cohort) were matched by age and sex to 42 HIV-positive controls without previously diagnosed lipodystrophy and to 13 HIV-negative controls. SettingTertiary care, university-based, fully dedicated HIV clinic. Main outcome measuresFrequency and magnitude of elevated blood pressure during highly active antiretroviral therapy. ResultsThere were 23 ± 16 and 22 ± 12 blood pressure measurements recorded per subject over 21 ± 11 and 22 ± 11 months for the HIV-positive cohort and HIV-positive controls, respectively. Three or more elevated readings occurred in 74% of the cohort and in 48% of the HIV-positive controls (P = 0.01) and accounted for 38 ± 25% versus 22 ± 26% (P = 0.01) of the total readings, respectively. The average of the three highest systolic readings (153 ± 17 versus 144 ± 15 mmHg;P = 0.01) and diastolic readings (92 ± 10 versus 87 ± 9 mmHg;P = 0.01) was greater for the cohort than for the HIV-positive controls. Family history of hypertension was more common in the cohort than in the controls but accounted for only 13% of the log odds ratio value for elevated blood pressure in the cohort. Systolic blood pressure was correlated with waist-to-hip ratios in the cohort (r = 0.45;P = 0.003) but not in the HIV controls (r = 0.06;P = 0.68) and tended to be related to fasting triglycerides (r = 0.34;P = 0.052) in subjects with HIV. ConclusionsElevated blood pressure may be linked to the metabolic disorders occurring in patients with HIV, as in the dysmetabolic syndrome.

Prospective, Intensive Study of Metabolic Changes Associated with 48 Weeks of Amprenavir-Based Antiretroviral Therapy

To determine whether a 48-week course of amprenavir-based antiretroviral therapy is associated with metabolic alterations, 14 clinically stable human immunodeficiency virus (HIV)-infected, protease inhibitor-naive adults initiated amprenavir-based triple therapy. Twelve subjects (86%) achieved HIV RNA levels of <400 copies/mL at week 24. Fasting glucose and insulin levels did not change. Insulin sensitivity did not decrease in the first 24 weeks, but a trend toward a decrease appeared at week 48. Six subjects experienced onset or worsening of glucose tolerance by week 24. Levels of fasting triglycerides and low-density lipoprotein, high-density lipoprotein, and total cholesterol increased. Bone mineral content, lean tissue, total fat, trunk fat, limb fat, and the ratio of trunk to limb fat increased at week 48. Amprenavir-based therapy was associated with increases in serum lipid levels but no short-term decrease in insulin sensitivity. A trend toward insulin resistance appeared late in the study following weight gain, particularly of trunk fat, but without loss of limb fat.