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.

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

Intravenous sulfamethoxazole and trimethoprim for serious gram-negative bacillary infection.

Intravenous therapy with sulfamethoxazole and trimethoprim cured seven patients with serious gram-negative infection. Three patients had bacteremia, three had pneumonia, and one each had meningitis, peritonitis, pyogenic liver abscesses, and urinary tract infection. Sulfamethoxazole and trimethoprim was selected in three patients with renal failure to avoid aminoglycoside-induced nephrotoxicity, in three patients because of penicillin allergy, and in two cases because of bacterial resistance to other readily available antibiotics. Adverse drug reactions occurred in three cases and included oral monilia, transient leukopenia, and fluid overload. In contrast to the new broad-spectrum cephalosporin antibiotics, sulfamethoxazole and trimethoprim costs two to 2 1/2 times less and has not been associated with the emergence of bacterial resistance during therapy. This may favor the use of parenteral sulfamethoxazole and trimethoprim for some patients with serious gram-negative infection.

Mycobacterial disease in patients with human immunodeficiency virus infection.

We compared the clinical features of disease due to tuberculosis and to Mycobacterium avium complex (MAC) in 94 patients with human immunodeficiency virus infection. Tuberculosis preceded the diagnosis of acquired immunodeficiency syndrome in 26 (67%) of 39 cases, compared with none of 55 with MAC infection. Chest roentgenographic findings suggested mycobacterial infection in 24 (83%) of 29 patients with pulmonary tuberculosis, compared with 7 (25%) of 28 with MAC infection. Sputum smears revealed acid-fast bacilli in 19 (83%) of 23 patients with pulmonary tuberculosis, but only 4 (16%) of 25 cases of pulmonary MAC infection. In 39 patients with tuberculosis, lymphadenitis and pleuritis were present in 13 (33%) and 8 (20%), respectively, but occurrence was rare in patients with MAC infection. In contrast, mycobacteremia was more frequent in MAC infection, occurring in 47 (85%) of 55 cases. In 5 patients, tuberculosis was unsuspected and probably contributed to death. These findings suggest that clinical features often distinguish tuberculosis from MAC infection in patients with human immunodeficiency virus infection. In addition, more intensive diagnostic use of sputum acid-fast smears may improve the outcome in patients with tuberculosis.

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.

Clinical features of 100 human immunodeficiency virus antibody-positive individuals from an alternate test site.

We evaluated 100 human immunodeficiency virus (HIV) antibody-positive persons from the only alternate test site in Los Angeles. Thirty-five subjects complained of systemic symptoms suggestive of HIV infection and 65 were completely asymptomatic. Irrespective of symptoms, the group as a whole demonstrated clinical and laboratory evidence of immunodeficiency. Eighty had generalized lymphadenopathy, 16 onychomycosis, six oral candidiasis, and two biopsy-proved Kaposi's sarcoma. Seventy-seven were anergic to seven intradermal antigens. Despite normal white blood cell counts in most subjects, the T-helper-cell count was less than 300/mm3 in 48% of asymptomatic and 46% of symptomatic subjects. The degree of immune depression was less severe but approximated that of patients with acquired immunodeficiency syndrome after Pneumocystis carinii pneumonia. We believe these findings justify the need for comprehensive medical evaluation and follow-up care for seropositive persons from alternate test sites.

Pseudomonas maltophilia causing heroin-associated infective endocarditis.

The association of Pseudomonas maltophilia endocarditis in three patients with recent history of intravenous drug abuse is reported. All three patients had abnormal heart valves (two prosthetic and one rheumatic). A prominent characteristic of this uncommon pathogen is its in vitro resistance to the commonly used antimicrobials. Cure was achieved in all three cases. In two cases, synergistic antibiotic combinations were used. In one case, plasmid-mediated resistance to amikacin sulfate (Amikan, British; no comparable US product) emerged during therapy. The two patients with prosthetic valves received combined surgical and antibiotic therapy.

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.

Changes in weight and lean body mass during highly active antiretroviral therapy.

BACKGROUND: Few studies have prospectively evaluated the impact of highly active antiretroviral therapy (HAART) on body weight and lean body mass (LBM) or explored the impact of baseline immunologic or virological changes on these parameters. METHODS: Adult AIDS Clinical Trials Group (ACTG) protocol 892 was a prospective, 48-week, multisite observational study of body composition conducted during 1997-2000 among 224 antiretroviral-naive and antiretroviral-experienced subjects coenrolled into various adult ACTG antiretroviral studies. Assessments included human immunodeficiency virus type 1 (HIV-1) RNA load (by polymerase chain reaction); T lymphocyte subset analysis; Karnofsky score; height (baseline only); weight, LBM, and fat (by bioelectrical impedance analysis); and functional performance (by questionnaire). RESULTS: Overall, only modest median increases in body weight (1.9 kg) and LBM (0.6 kg) occurred after 16 weeks of therapy. Significantly greater median increases in body weight (2.1 vs. 0.5 kg; P=.045) occurred in subjects who achieved virological suppression (HIV-1 RNA load, <500 copies/mL) at week 16 than in subjects who did not. Subjects who were antiretroviral naive at baseline gained more weight (median increase in body weight, 2.6 vs. 0.0 kg; P<.001) and LBM (1.0 vs. 0.1 kg; P=.002) after 16 weeks of treatment than did subjects who were antiretroviral experienced. Subjects with lower baseline CD4 cell counts (<200 cells/mm3) and subjects with higher baseline HIV-1 RNA loads (> or =100,000 copies/mL) were more likely to show increases in LBM of >1.5 kg (P=.013 and P=.005, respectively). CONCLUSIONS: HAART had modestly favorable effects on body composition, particularly in patients with greater pretreatment immunocompromise and virological compromise. The difference between antiretroviral-naive and antiretroviral-experienced subjects with regard to the ability to achieve increased body weight and LBM requires more study.

The use of a sensitive equilibrium dialysis method for the measurement of free testosterone levels in healthy, cycling women and in human immunodeficiency virus-infected women.

Measurements of total and free testosterone levels in women have lacked precision and accuracy because of limited assay sensitivity. The paucity of normative data on total and free testosterone levels in healthy women has confounded interpretation of androgen levels in women with human immunodeficiency virus (HIV) infection and other disease states. Therefore, the objectives of this study were to develop sensitive assays for the measurement of the low total and free testosterone levels in women to define the range for these hormones during the normal menstrual cycle and assess the total and free testosterone levels in HIV-infected women. By using a larger volume of serum, increasing the incubation time, and reducing the antibody concentration, the sensitivity of the total testosterone assay was increased to 0.008 nmol/L, and that of the free testosterone assay was increased to 2 pmol/L. The mean percent free testosterone was 1.0 +/- 0.1% of the total testosterone. Serum total and free testosterone levels in the follicular and luteal phases were not significantly different, but both demonstrated a modest preovulatory increase, 3 days before the LH peak. Serum total [0.50 +/- 0.32 (14.60 +/- 9.22) vs. 1.2 +/- 0.7 nmol/L (34.3 +/- 21.0 ng/dL); P < 0.0001] and free testosterone levels (5.56 +/- 2.70 (1.58 +/- 0.80) vs. 12.8 +/- 5.5 pmol/L (3.4 +/- 1.7 pg/mL); P < 0.0001) were significantly lower in HIV-infected women (n = 37) than in healthy women (n = 34). Serum total and free testosterone levels were also significantly lower in HIV-infected women who were menstruating normally. There were no significant differences in serum total and free testosterone levels between those who had lost weight and those who had not. Testosterone levels correlated inversely with plasma HIV ribonucleic acid copy number. Serum FSH, but not LH, levels were significantly higher in HIV-infected women than in controls. Using assays with sufficient sensitivity, we defined the range for total and free testosterone levels during the normal menstrual cycle. Serum total and free testosterone levels are lower in HIV-infected women and correlate inversely with plasma HIV ribonucleic acid levels. The hypothesis that androgen deficiency contributes to wasting in HIV-infected women remains to be tested.

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.

Meningitis caused by Streptococcus bovis.

Streptococcus bovis was isolated from the CSF of a 66-year-old man with meningitis. His clinical appearance was unusual in that he lacked typical signs and symptoms of pyogenic meningitis. Streptococcus bovis was also recovered from his blood, which suggested that bacterial endocarditis was the source of his CNS infection. He was cured after four weeks of therapy with intravenous penicillin G potassium. This is the fourth reported case of meningitis caused by S bovis. The previous three patients also had endocarditis caused by S bovis. Because of the reported propensity of S bovis to infect heart valves and the frequent association of S bovis bacteremia with malignant gastrointestinal (GI) tract tumors, recovery of this organism form CSF should prompt a search for bacterial endocarditis and occult GI cancer.

Optic neuropathy and paratrigeminal syndrome due to Aspergillus fumigatus.

Chronic Aspergillus meningitis and cerebral vasculitis occurred in a 67-year-old man. He experienced periorbital pain that increased in severity during a ten-month period. Although no focal neurologic deficits were initially present, oculosympathetic paresis, corneal hypesthesia, and optic neuropathy developed. This is the first report, to our knowledge, of paratrigeminal syndrome with optic neuropathy due to aspergillosis. The case was also unusual because it was chronic and there was no extracerebral infection or predisposing factors, such as underlying malignancy or collagen vascular disease.

Cytomegalovirus and Candida esophagitis in patients with AIDS.

We define the clinical importance of cytomegalovirus (CMV) in the natural history of patients with concomitant candida and CMV infection of the esophagus. Prospective evaluation was made of patients with Candida and CMV esophagitis enrolled in a trial of antifungal therapy for Candida esophagitis. Retrospective review was also made of the course of patients who had been found to have both Candida and CMV infection during a previous prospective endoscopic study investigating the etiology of esophageal symptoms in HIV infection. Ten (21%) of 48 patients with Candida esophagitis in the prospective study had evidence of esophageal CMV (nine by culture, one by histology). One died after 4 weeks of therapy, with minimal retrosternal pain. None of the remaining nine had any symptoms or gross CMV esophagitis after antifungal therapy. Thirteen other patients with CMV and Candida were included in the retrospective review (mean follow-up of 8 months). Eight patients received antifungal therapy alone: six (CMV determined by histology in three and by culture in three) had symptomatic resolution; one (CMV by culture) had ongoing symptoms, and a second endoscopy showed an esophageal ulcer due to CMV (histology and culture); and one had ongoing symptoms but a negative repeat endoscopy. Two died without receiving treatment, and three were treated with antifungal and anti-CMV therapy together because of concurrent CMV retinitis (esophageal symptoms resolved in all three). Thus, CMV was of clinical importance in the esophagus in only one of 18 patients with CMV and Candida who received antifungal therapy alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Dapsone as a single agent is suboptimal therapy for Pneumocystis carinii pneumonia.

In a prospective, noncomparative study, seven patients with mild Pneumocystis carinii pneumonia, characterized by room air arterial PO2 greater than 60 mm Hg at the time of presentation, were treated with dapsone alone at a dose of 200 mg daily. Two of the seven patients required mechanical ventilation for respiratory failure on day 5 of dapsone therapy; both died. Four patients experienced major side effects during dapsone therapy. None of the seven patients successfully completed a full course of therapy with dapsone. We conclude that high-dose, single-agent dapsone is not suitable for further study as therapy for Pneumocystis carinii pneumonia.

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.

Intravenous trimethoprim-sulfamethoxazole therapy for Pneumocystis carinii pneumonia.

Twenty-nine immunocompromised patients were treated with intravenous trimethoprim-sulfamethoxazole for possible Pneumocystis carinii pneumonia. The diagnosis was established in 15 severely hypoxemic patients with lymphoreticular malignancy or cardiac transplants by open lung biopsy or transthoracic needle aspirate. In 13 (87 percent) of the 15, the response to therapy was rapid. They became afebrile in a mean of 2.1 days, showed improved arterial blood oxygenation in 4.7 days and improvements on the chest roentgenogram in 4.3 days. Eight (53 percent) of the 15 survived and were clinically cured. Five other patients with documented P. carinii infection improved clinically but subsequently died of other causes. Postmortem examination in these showed no P. carinii cysts. Two patients with P. carinii pneumonia died soon after therapy was started and had P. carinii cysts in lung tissue at autopsy. The combined clinical and microbiologic response of 87 percent equals or exceeds that of other reported treatment regimens. Intravenous trimethoprim-sulfamethoxazole may, therefore, be the most ideal therapy for severely ill adults with P. carinii pneumonia. Second lung biopsies in 12 patients on therapy showed that P. carinii cysts were rarely found after several days of treatment. This suggests that lung tissue may be falsely negative for P. carinii cysts in persons treated empirically but who later undergo lung biopsy.

Efficacy of amdinocillin and lack of nephrotoxicity when combined with a second beta-lactam antibiotic for therapy of serious gram-negative bacillary infections.

Seventy-eight patients with serious gram-negative bacillary infections were assigned at random to receive either amdinocillin or an aminoglycoside. In addition, each patient was also given a broad-spectrum penicillin or cephalosporin antibiotic. The clinical response to treatment was comparable in the two groups. Cures were effected in 35 (92 percent) of 38 patients treated with amdinocillin and a beta-lactam antibiotic, compared with 37 (93 percent) of 40 patients who were treated with an aminoglycoside/beta-lactam combination. For the entire group, only five (7 percent) of the 75 infecting organisms were resistant in vitro to the treatment beta-lactam or amdinocillin combination, and similarly only two (3 percent) organisms were resistant to the treatment aminoglycoside (p = 0.44). Although drug-related toxicity occurred with equal frequency in the two groups, six patients treated with an aminoglycoside experienced nephrotoxicity compared with none of the patients who received amdinocillin (p = 0.034). Thus, amdinocillin plus a broad-spectrum beta-lactam antibiotic may provide suitable empiric therapy for many patients with presumed gram-negative infection and so avoid the risk of aminoglycoside-induced nephrotoxicity.

Cefoperazone for empiric therapy in patients with impaired renal function.

Thirty-five patients with serious infections and impaired renal function were treated empirically with 2 to 8 g of cefoperazone per day. Infections included sepsis in 14, nonbacteremic urinary infections in nine, pneumonia in five, intra-abdominal infection in five, fasciitis in one, and malignant otitis externa in one. The average age of this group was 64.3 years, 25 had ultimately fatal underlying diseases, and their average serum creatinine level was 5.2 mg/dl. Infections were caused by Enterobacteriaceae in 23 patients, Streptococcus faecalis in five, Pseudomonas aeruginosa in four, Staphylococcus aureus in four, Hemophilus influenzae in three, and Staphylococcus epidermidis, Streptococcus pneumoniae, and Clostridium sordelli in one each. Overall, 32 patients had clinical and microbiologic cures, two had improvement, and one had failure. Hypoprothrombinemia occurred in 18 of 28 patients not given vitamin K for prophylaxis and occurred more often in those with serum albumin concentrations below 3.5 g/dl. Prothrombin times returned to normal within 36 hours of treatment with vitamin K, although two patients experienced mild hematemesis. In anicteric patients with liver function abnormalities, 2 g every 12 hours produced peak and trough serum concentrations that averaged 254 and 125 micrograms/ml, respectively, compared with 179.5 and 19.5 micrograms/ml, respectively, in five with normal liver function test results. In jaundiced patients treated with 1 g every 12 hours, trough concentrations were comparably elevated. Serum concentrations did not correlate with hypoprothrombinemia, but high levels throughout the dosing interval may have contributed to the excellent cure rate in this study.

The tolerance for zidovudine plus thrice weekly or daily trimethoprim-sulfamethoxazole with and without leucovorin for primary prophylaxis in advanced HIV disease. California Collaborative Treatment Group.

PURPOSE: Trimethoprim-sulfamethoxazole (TMP/SMX) is the preferred agent for prophylaxis of Pneumocystis carinii pneumonia (PCP) in patients with HIV infection, but frequent adverse events limit its usefulness. Intermittent dosing and supplementation with leucovorin have been tried in attempts to improve tolerance. We evaluated these strategies in persons with advanced HIV disease. METHOD: One hundred seven patients were enrolled. All had HIV infection, < 200 CD4+ lymphocytes per mm3, and no history of PCP. Fifty-two were randomized to TMP/SMX twice daily (BID); of these, 26 were randomized to leucovorin with each dose. Fifty-five patients were randomized to TMP/SMX (BID) 3 times per week; of these, 27 were randomized to leucovorin with each dose. All patients took zidovudine concurrently. RESULTS: The 24-week risk of discontinuation due to protocol-defined limiting toxicity was 24% with thrice-weekly TMP/SMX versus 42% with daily TMP/SMX (risk ratio 0.4; 95% CI 0.2 to 1.0). The risks of discontinuation for any reason were 41% and 59% (risk ratio 0.4; 95% CI 0.2 to 0.8). Clinical toxicity, such as headache and gastrointestinal distress, accounted for the observed difference in tolerance between dosing regimens. The 24-week risk of discontinuation due to protocol-defined toxicity was 33% in both the leucovorin and non-leucovorin groups (risk ratio 1.1; 95% CI 0.5 to 2.5). The risks of discontinuation for any reason were 53% and 47% (risk ratio 0.8; 95% CI 0.3 to 1.7). CONCLUSION: Intermittent therapy with TMP/SMX BID thrice weekly is better tolerated than daily BID therapy. Leucovorin use does not improve tolerance for chronic TMP/SMX dosing in AIDS, even among patients taking tablets daily.