A novel biopsy method to increase yield of subcutaneous abdominal adipose tissue.

Collection of abdominal subcutaneous adipose tissue (SAT) for research testing is traditionally performed using punch biopsy or needle aspiration techniques, yielding small amounts of very superficial SAT (100-500 mg). Although liposuction techniques can be used to obtain large amounts of SAT, these approaches can compromise the integrity of the adipose tissue. Therefore, we investigated a novel method using a 6-mm Bergström side-cutting biopsy needle to acquire suitable amounts of intact abdominal SAT for multiple complex studies such as flow cytometry, RNA extraction, ex vivo expression of molecular and post-translational protein mediators, and histology. Fifty biopsies were obtained from 29 participants using a Bergström biopsy needle, applying transient manual suction and shearing large pieces of fat within the inner-cutting trochar. Eighteen of the biopsies were performed under ultrasound guidance, whereby we successfully sampled deep SAT (dSAT) from below Scarpa's fascia. The average weight of SAT sampled was 1.5 ± 0.4 g. There was no clinically important bleeding or ecchymosis on the abdominal wall and no infection occurred with this procedure. The 6-mm Bergström biopsy needle yielded substantially more SAT than what has been obtained from superficial procedures and, for the first time, allowed sampling of dSAT by a percutaneous approach.

Cardiometabolic risks during anabolic hormone supplementation in older men.

OBJECTIVE: To determine the cardiometabolic risks of testosterone and growth hormone (GH) replacement therapy to youthful levels during aging. DESIGN AND METHODS: A double-masked, partially placebo controlled study in 112 men 65-90 years-old was conducted. Transdermal testosterone (5 g vs. 10 g/day) using a Leydig Cell Clamp and subcutaneous recombinant GH (rhGH) (0 vs. 3 vs. 5 µg/kg/day) were administered for 16-weeks. Measurements included testosterone and IGF-1 levels, body composition by DEXA, and cardiometabolic risk factors (upper body fat, blood pressure, insulin sensitivity, fasting triglycerides, HDL-cholesterol, and serum adiponectin) at baseline and after 16 weeks of treatment. RESULTS: Some cardiometabolic factors improved (total and trunk fat, triglycerides, HDL-cholesterol) and others worsened (systolic blood pressure, insulin sensitivity index [QUICKI], adiponectin). Cardiometabolic risk composite scores (CRCSs) improved (-0.69 ± 1.55, P < 0.001). In multivariate analyses, QUICKI, triglycerides, and HDL-cholesterol contributed 33%, 16%, and 14% of the variance in CRCS, respectively. Pathway analyses indicated that changes in fat and lean mass were related to individual cardiometabolic variables and CRCS in a complex manner. Changes in BMI, reflecting composite effects of changes in fat and lean mass, were more robustly associated with cardiometabolic risks than changes in fat mass or LBM individually. CONCLUSIONS: Testosterone and rhGH administration was associated with diverse changes in individual cardiometabolic risk factors, but in aggregate appeared not to worsen cardiometabolic risk in healthy older men after 4-months. The long-term effects of these and similar anabolic therapies on cardiovascular events should be investigated in populations with greater functional limitations along with important health disabilities including upper body obesity and other cardiometabolic risks.

Hormone therapy attenuates exercise-induced skeletal muscle damage in postmenopausal women.

Hormone therapy (HT) is a potential treatment to relieve symptoms of menopause and prevent the onset of disease such as osteoporosis in postmenopausal women. We evaluated changes in markers of exercise-induced skeletal muscle damage and inflammation [serum creatine kinase (CK), serum lactate dehydrogenase (LDH), and skeletal muscle mRNA expression of IL-6, IL-8, IL-15, and TNF-alpha] in postmenopausal women after a high-intensity resistance exercise bout. Fourteen postmenopausal women were divided into two groups: women not using HT (control; n = 6, 59 +/- 4 yr, 63 +/- 17 kg) and women using traditional HT (HT; n = 8, 59 +/- 4 yr, 89 +/- 24 kg). Both groups performed 10 sets of 10 maximal eccentric repetitions of single-leg extension on the Cybex dynamometer at 60 degrees /s with 20-s rest periods between sets. Muscle biopsies of the vastus lateralis were obtained from the exercised leg at baseline and 4 h after the exercise bout. Gene expression was determined by RT-PCR for IL-6, IL-8, IL-15, and TNF-alpha. Blood draws were performed at baseline and 3 days after exercise to measure CK and LDH. Independent t-tests were performed to test group differences (control vs. HT). A probability level of P

Elevated blood pressure in subjects with lipodystrophy.

OBJECTIVES: To assess the prevalence of elevated blood pressure in patients with lipodystrophy. DESIGN: Case-control study. PARTICIPANTS: Forty-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. SETTING: Tertiary care, university-based, fully dedicated HIV clinic. MAIN OUTCOME MEASURES: Frequency and magnitude of elevated blood pressure during highly active antiretroviral therapy. RESULTS: There 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. CONCLUSIONS: Elevated blood pressure may be linked to the metabolic disorders occurring in patients with HIV, as in the dysmetabolic syndrome.

Urinary cytokines for assessing inflammation in HIV-associated wasting.

The relationship between cytokines and HIV-related weight loss has not been well established. Unlike most cytokines that are secreted in a paracrine manner, IL-6, sTNFR-II, and IL-1ra are readily detected in the systemic circulation and serve as markers of the inflammatory response. Twenty-four-hour urine concentrations of these proteins are believed to provide an integrative assessment of their systemic levels over the preceding hours. We sought to determine whether spot measurements of IL-6, sTNFR-II, and IL-1ra could be related to subsequent 24 h concentrations and prior weight loss. Eighteen subjects with severe wasting (average BMI=18+/-3 kg/m2with 19+/-13 kg of weight loss) and six HIV-negative healthy subjects were tested. Compared to values in controls, 24-h urinary concentrations of the three proteins adjusted for creatinine excreted were elevated in 44%, 89%, and 72% of patients, respectively. Twenty-four-hour concentrations were highly correlated with the spot concentrations (r=0.80, 0.87, 0.84, respectively, P<0.001). IL-1ra concentrations (24 h and spot) were correlated with weight loss in the previous 6 months, lifetime rate of weight loss and the 6 month rate of weight loss (spot: r=0.66, 0.73, 0.68, respectively, P< or =0.001). These data suggest that spot urinary collections can be used to estimate 24 h excretion rates. This strategy may be useful in assessing the inflammatory response in HIV-associated wasting.

Metabolic Syndromes Associated With HIV: Mitigating the Side Effects of Drug Therapy.

HIV infection and highly active antiretroviral therapy (HAART) are associated with a variety of metabolic disorders such as AIDS wasting syndrome, cachexia, sarcopenia, metabolic dysregulation, lipodystrophy, abnormalities of serum lipids, and lactic acidosis. Adjunctive therapies (eg, diet, antilipid therapy), risk-factor modification (eg, smoking cessation, blood pressure control), aerobic exercise, and anabolic treatments can be used to mitigate the effects of HIV infection and the adverse effects of HAART, thereby improving long-term health in individuals infected with HIV.

Efficacy of azithromycin in prevention of Pneumocystis carinii pneumonia: a randomised trial. California Collaborative Treatment Group.

BACKGROUND: Azithromycin in combination with sulphonamides is active against Pneumocystis carinii pneumonia (PCP) in animals. We assessed the clinical efficacy of azithromycin for PCP prophylaxis in human beings. METHODS: We identified HIV-1-infected patients with PCP during a prospective randomised trial comparing azithromycin, rifabutin, and the two drugs in combination for prevention of disseminated Mycobacterim avium infection. Patients had CD4-cell counts less than 100/microL at entry and received PCP prophylaxis according to the standard practice of their clinician. Analysis was by intention to treat. FINDINGS: Patients receiving azithromycin, either alone (n=233) or in combination with rifabutin (n=224), had a 45% lower risk of developing PCP than those receiving rifabutin alone (n=236; p=0.008). Compared with rifabutin alone, hazard ratio for azithromycin was 0.54 (95% CI 0.32-0.94), for azithromycin plus rifabutin was 0.55 (0.32-0.94), and for regimens containing azithromycin was 0.55 (0.35-0.86). The most common side-effects involved the gastrointestinal tract with dose-limiting toxicities, and were mainly seen in patients receiving combination therapy. INTERPRETATION: Azithromycin as prophylaxis for M. avium complex disease provides additional protection against P. carinii over and above that of standard PCP prophylaxis. Use of azithromycin is beneficial only as primary prophylaxis.

Effects of pharmacological doses of nandrolone decanoate and progressive resistance training in immunodeficient patients infected with human immunodeficiency virus.

This nonplacebo-controlled, open label, randomized study was conducted to test the hypotheses that pharmacological doses of nandrolone decanoate would increase lean body tissue, muscle mass, and strength in immunodeficient human immunodeficiency virus-infected men, and that these effects would be enhanced with progressive resistance training (PRT). Thirty human immunodeficiency virus-positive men with fewer than 400 CD4 lymphocytes/mm3 were randomly assigned to receive weekly injections of nandrolone alone or in combination with supervised PRT at 80% of the one-repetition maximum three times weekly for 12 weeks. Total body weight increased significantly in both groups (3.2 +/- 2.7 and 4.0 +/- 2.0 kg, respectively; P < 0.001), with increases due primarily to augmentation of lean tissue. Lean body mass determined by dual energy x-ray absorptiometry increased significantly more in the PRT group (3.9 +/- 2.3 vs. 5.2 +/- 5.7 kg, respectively; P = 0.03). Body cell mass by bioelectrical impedance analysis increased significantly (P < 0.001) in both groups (2.6 +/- 1.0 vs. 2.9 +/- 0.8 kg), but to a similar magnitude (P = NS). Significant increases in cross-sectional area by magnetic resonance imaging of total thigh muscles (1538 +/- 767 and 1480 +/- 532 mm2), quadriceps (705 +/- 365 and 717 +/- 288 mm2), and hamstrings (842 +/- 409 and 771 +/- 295 mm2) occurred with both treatment strategies (P < 0.001 for the three muscle areas); these increases were similar in both groups (P = NS). By the one-repetition method, strength increased in both upper and lower body exercises, with gains ranging from 10.3-31% in the nandrolone group and from 14.4-53.0% in the PRT group (P < 0.006 with one exception). Gains in strength were of significantly greater magnitude in the PRT group (P < or = 0.005 for all comparisons), even after correction for lean body mass. Thus, pharmacological doses of nandrolone decanoate yielded significant gains in total weight, lean body mass, body cell mass, muscle size, and strength. The increases in lean body mass and muscular strength were significantly augmented with PRT.

Pharmacokinetics of trimetrexate and dapsone in AIDS patients with Pneumocystis carinii pneumonia.

The objective of this study was to determine the pharmacokinetics of trimetrexate and dapsone in AIDS patients with moderate to severe pneumocystis pneumonia. Trimetrexate, leucovorin, and dapsone were administered for 21 +/- 3 days in the following doses: trimetrexate glucuronate, 45 mg/m2; leucovorin, 20 mg/m2; and dapsone, 100 mg daily. The pharmacokinetics of trimetrexate, dapsone, and dapsone's metabolite, monoacetyldapsone, were determined at three separate periods over the course of treatment. Serial blood samples were obtained over 24 hours after dosing and analyzed for trimetrexate, dapsone, and monoacetyldapsone, and pharmacokinetic parameters were determined. The mean parameters obtained for the early, mid-, and late collection periods were the following: trimetrexate: t1/2 = 8.29, 9.15, 10.00 hr; AUC = 16.85, 22.38, 24.49 mg.hr/l; CI = 5.58, 4.14, 3.96 l/hr, respectively. DDS: t1/2 = 14.99, 16.59, 15.13 hr; AUC = 30.60, 35.29, 36.08 mg.hr/l; CI = 3.82, 3.49, 3.01 l/hr, respectively. Monoacetyldapsone: t1/2 = 20.25, 18.66, 16.32 hr; AUC = 24.05, 24.06, 23.86 mg.hr/l, respectively. No statistically significant changes in pharmacokinetics for trimetrexate or dapsone were observed over the 21 +/- 3 day course of treatment. The results suggest that there are no major interactions between trimetrexate and dapsone when administered together in acutely ill patients.

Successful short-term suppression of clarithromycin-resistant Mycobacterium avium complex bacteremia in AIDS. California Collaborative Treatment Group.

During a randomized study of clarithromycin plus clofazimine with or without ethambutol in patients with AIDS and Mycobacterium avium complex (MAC) bacteremia, eight participants received additional antimycobacterial drugs following the detection of a clarithromycin-resistant isolate (MIC, > 8 micrograms/mL). A macrolide (seven received clarithromycin, one azithromycin) and clofazimine were continued; additional treatment included various combinations of ethambutol, ciprofloxacin, amikacin, and rifabutin. After the detection of a resistant isolate and before receipt of additional antimycobacterials, the median peak MAC colony count in blood was 105 cfu/mL (range, 8-81,500 cfu/mL). After additional antimycobacterials, the median nadir MAC colony count was 5 cfu/mL (range, 0-110 cfu/mL). Five (63%) of eight patients had a > or = 1 log10 decrease, including two who achieved negative blood cultures; all of these responses occurred in patients originally assigned to clarithromycin plus clofazimine. Treatment of clarithromycin-resistant MAC bacteremia that emerges during clarithromycin-based treatment can decrease levels of bacteremia and transiently sterilize blood cultures.

Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with AIDS.

We compared the efficacy of a 400-mg once-weekly dosage versus a 200-mg daily dosage of fluconazole for the prevention of deep fungal infections in a multicenter, randomized, double-blind trial of 636 human immunodeficiency virus-infected patients to determine if a less intensive fluconazole regimen could prevent these serious but relatively infrequent complications of AIDS. In the intent-to-treat analysis, a deep fungal infection developed in 17 subjects (5.5%) randomly assigned to daily fluconazole treatment and in 24 (7.7%) given weekly fluconazole during 74 weeks of follow-up (risk difference, 2.2%; 95% confidence interval [CI], -1.7% to 6.1%). Thrush occurred twice as frequently in the weekly versus daily fluconazole recipients (hazard ratio, 0.59; 95% CI, 0.40-0.89), and in a subset of patients evaluated, fluconazole resistance was infrequent. Fluconazole administered once weekly is effective in reducing deep fungal infections in patients with AIDS, but this dosage is less effective than the 200-mg-daily dosage in preventing thrush.

Levels of HIV RNA are quantitatively related to prior weight loss in HIV-associated wasting.

Thirty-three patients referred to a wasting clinic were evaluated to assess whether levels of HIV RNA were related to the magnitude of prior weight loss. Their median RNA level was 46,887 gene copies/ml (range, <200-510,070 gene copies/ml) at the time of referral. Patients had lost 10.5 +/- 6.4 kg over 461 +/- 304 days. RNA levels were correlated with the absolute amount and percentage of weight lost as well as the difference in body mass index (BMI) at the prior maximal and minimal recorded weights (r = 0.7, 0.67, 0.69; p = .0001 for the comparisons). The magnitude of these changes increased across strata of HIV RNA levels (p < or = .004), previously defined as associated with increasing risk for disease progression. The other parameter that could be associated with weight loss was the CD4 lymphocyte count (r = -0.43; p = .01). Low levels of testosterone and measures of body cell mass, fat free mass, or fat mass within 6 weeks of the RNA level could not be related to weight loss, change in BMI, or RNA levels. Thirty-two of the patients had chronic, relentless weight loss; in 15 of these subjects, no apparent secondary opportunistic complications were associated with weight loss or gastrointestinal symptoms to impair energy intake. Levels of HIV replication appear to be causally related to the magnitude of weight loss in some patients with wasting.

Human immunodeficiency virus-associated wasting and mechanisms of cachexia associated with inflammation.

Profound weight loss and progressive depletion of muscle mass is a common sequela of chronic diseases such as cancer, tuberculosis, and human immunodeficiency virus (HIV) infection. Studies of HIV-associated wasting have revealed several possible mechanisms. Alterations in anabolic hormones, energy intake, energy expenditure, and production of proinflammatory cytokines, which cause cachexia, may contribute to wasting in HIV-infected patients. These studies have revealed the complexity of the interactions between cytokines and the hormones that typically regulate catabolic-anabolic homeostasis. Despite this complexity, HIV-associated wasting should be manageable. Several strategies are currently under investigation, including anabolic steroid and human growth hormone therapy, appetite stimulants, nutritional supplementation, and cytokine antagonists. Some of these approaches have shown early promise. Further research in these areas should facilitate development of effective intervention strategies and lead to improvements in quality of life for patients suffering from wasting syndromes.

A randomized, double-blind trial of valaciclovir prophylaxis for cytomegalovirus disease in patients with advanced human immunodeficiency virus infection. AIDS Clinical Trials Group Protocol 204/Glaxo Wellcome 123-014 International CMV Prophylaxis Study Group.

Cytomegalovirus (CMV) disease is a common complication of advanced human immunodeficiency virus (HIV) infection. Administration of oral valaciclovir, a valine ester of acyclovir, achieves sufficient plasma acyclovir levels to inhibit many clinical isolates. Acyclovir has been associated with enhanced survival in AIDS but not with CMV disease prevention. CMV-seropositive patients (1227) with CD4 cell counts <100/mm3 were enrolled in a randomized, double-blind trial. Valaciclovir, 8 g/day, was compared with acyclovir, 3.2 or 0.8 g/day, for CMV prevention; all three arms were compared for survival. The confirmed CMV disease rate was 11.7% among valaciclovir recipients and 17.5% in the pooled acyclovir arms, a 33% reduction in risk. Time to confirmed CMV disease was significantly longer for the valaciclovir group (P = .03). A trend toward earlier mortality for valaciclovir recipients was seen (P = .06). Toxicity and earlier medication discontinuation were more common in this group. Valaciclovir significantly reduces the risk of CMV disease. Further exploration of a better-tolerated dose is warranted.

Metabolic complications of antiretroviral therapies.

AIDS: Reports of metabolic disorders, such as diabetes mellitus and hyperlipidemia, occurring during treatment with protease inhibitor (PI) regimens are prompting patients and providers to try to better understand the links between these disorders and antiretroviral treatments. The Food and Drug Administration (FDA) first reported PI-associated diabetes in June 1997. Diabetes mellitus can be managed by controlling diet and exercise, or by supplementing treatment with oral hypoglycemic drugs. Hypertriglyceridemia has also been associated with PI therapies, and is apparent even in patients experiencing good results from antiretroviral therapy. Treatment for hypertriglyceridemia encompasses monitoring diet and exercise, limiting alcohol, watching hypertension, and quitting smoking. Patients at higher risk for pancreatitis can consider using lipid-lowering drugs and fibric acid derivatives. Alterations in fat distribution have also been linked to PI use, particularly in the back of the neck and upper back, and abdominal area. Researchers have seen evidence of anomalous fat distribution in some patients prior to PI treatment. Management has not consistently been remedied by diet and exercise. Sustaining overall health, reducing blood lipids, and controlling risk factors for cardiovascular disease need to be implemented. Unless the abnormalities are severe and potentially harmful to the patient, it is not commonly recommended to change the PI treatment.^ieng

A randomized evaluation of ethambutol for prevention of relapse and drug resistance during treatment of Mycobacterium avium complex bacteremia with clarithromycin-based combination therapy. California Collaborative Treatment Group.

Patients with AIDS and Mycobacterium avium complex (MAC) bacteremia are at high risk for relapse and emergence of resistant isolates during monotherapy with clarithromycin. Ninety-five AIDS patients with MAC bacteremia received clarithromycin plus clofazimine, with or without ethambutol, in a prospective, multicenter, randomized open-label trial. Of 80 patients with positive baseline cultures, sterilization or a 2 log10 reduction in colony-forming units of MAC in two consecutive blood cultures occurred in 69% of both groups. There were nine relapses in the two-drug arm and three in the three-drug arm. Kaplan-Meier estimates of risk of relapse at 36 weeks were 68% and 12%, respectively (P = .004). All relapse isolates were resistant to clarithromycin. Median time to clarithromycin resistance was 16 weeks with two drugs and 40 weeks with three drugs (P = .004). Ethambutol reduced relapses and emergence of clarithromycin resistance and should be considered an essential component of clarithromycin-based therapies for MAC bacteremia.

A population pharmacokinetic model of trimethoprim in patients with pneumocystis pneumonia, made with parametric and nonparametric methods.

A population pharmacokinetic model of intravenously and orally administered trimethoprim in patients with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia has been made using a parametric iterative two-stage Bayesian and a nonparametric expectation maximization computer program. When good information was present in the serum level data, both methods obtained similar results. With the nonparametric expectation maximization program, the median apparent rate constant for absorption (Ka) was 1.602 hr-1, median slope (Ks) of the relationship between creatinine clearance and elimination was 0.001168 hr-1, median apparent volume of distribution (Vs) was 1.058 l/kg, and median fraction of oral dose absorbed (Fa) was 0.955. These results permit dosage individualization adjusted to body weight and renal function to achieve chosen serum level peak and trough goals. Peak goals of 9 ug/ml and trough goals of 5 ug/ml appear reasonable for most patients in this population, and should permit most to complete an effective course of therapy with a reduced risk for treatment-terminating hematologic toxicity. However, therapeutic goals should always be selected based on each patient's apparent need for the drug and the risk of toxicity that is justifiably acceptable to obtain the expected benefits of the drug.

Pneumocystis carinii pneumonia masquerading as tuberculosis.

Recent laboratory studies indicate that genetic diversity exists in human strains of Pneumocystis carinii. Structural and functional variability in infecting strains could result in differences in host-parasite interactions and the natural history of P carinii pneumonia. We report 5 unusual cases in which the clinical presentation mimicked tuberculosis. All patients were cared for at a university-based public hospital clinic in Los Angeles, Calif, during a 2-year period. These patients were chronically ill, had lost weight, and each had cavities or cystic spaces as the primary radiographic findings. None were receiving aerosol pentamidine and only one had a history of smoking. Four patients were initially treated for tuberculosis and the fifth for disseminated Mycobacterium avium complex. Pneumocystis carinii was the only pathogen identified in each case. The unusual clinical presentations delayed the diagnosis of P carinii in all 5 cases. Practitioners must be aware of the variable presentations of P carinii pneumonia.

T cell receptor (TCR) BV gene repertoires and clonal expansions of CD4 cells in patients with HIV infections.

Despite extensive investigation, the pathogenesis of T cell depletions that characterize AIDS has not been elucidated. To study this process further, we evaluated T cell antigen receptor beta-chain variable gene (TCRBV) repertoires in peripheral blood lymphocytes (PBL) of 23 HIV-infected patients. Expression levels of 28 TCRBV were determined by multiprobe RNase protection assay after polymerase chain reaction (PCR) amplifications. Abnormal expansions (> 2 s.d. from mean normal values) were frequent in HIV CD4, accounting for 26% of total measured TCRBV in this population. The number and magnitude of abnormalities among individuals were inversely proportional to their CD4 counts (P < 0.012 and P < 0.01, respectively). While abnormalities were not randomly distributed among TCRBV subfamilies, no particular genes were expanded or contracted among all patients. Only 14% of CD8 TCRBV were proportionally expanded (P < 0.01 compared with CD4), and there were limited concordances between paired CD8 and CD4 repertoires among individuals. CDR3 length analyses and TCRBV sequencing showed that most CD4 expansions comprised clonal or oligoclonal populations. Thus, T cell responses in HIV patients are characterized by severe TCRBV biases and clonal expansions among CD4 subsets, and these processes are exaggerated with disease progression. The heterogeneity and oligoclonality of the TCRBV expansions are consistent with responses to HIV-encoded or other conventional antigens rather than superantigenic effects. The presence of CD4 clonal proliferations in these patients may be important in the pathogenesis of HIV, and the absence or reduction of many T cell specificities due to oligoclonal expansions may increase susceptibility to opportunistic infections.

Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group.

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.