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* Objective: To determine the quantitative microbiologic response and the clinical response of patients with Mycobacterium avium complex bacteremia and AIDS to an oral antimycobacterial regimen. * Design: A phase II, multicenter clinical trial. * Setting: Four university-affiliated medical centers. * Patients: Forty-one patients with HIV infection who had at least two consecutive blood cultures positive for M. avium complex and who had not received previous antimycobacterial therapy were enrolled in the study. Thirty-one patients were evaluable with regard to the efficacy of the oral regimen. * Interventions: Patients received a combination of orally administered rifampin (600 mg), ethambutol (15 mg/kg body weight), clofazimine (100 mg once daily), and ciprofloxacin (750 mg twice daily) for 12 weeks. Parenterally administered amikacin, 7.5 mg/kg daily for 4 weeks after the first 4 weeks of oral therapy, was used at the discretion of the individual investigator. * Measurements: Clinical symptoms, Karnofsky scores, and adverse events were monitored. Colony counts for M. avium complex were determined. * Main Results: The mean logarithmic (log) baseline colony count decreased from 2.1 to 0.7 after 4 weeks of oral therapy (P < 0.001). Suppression of bacteremia was sustained throughout therapy. Thirteen patients (42%) became culture negative during therapy. The mean duration of treatment was 9.7 weeks. Nineteen evaluable patients (61%) completed 12 weeks of therapy. Adverse reactions to one or more agents were common. * Conclusions: A rapid reduction in symptoms and bacteremia can be achieved as early as week 2 of therapy using an oral regimen of rifampin, ethambutol, clofazimine, and ciprofloxacin. Colony counts rose dramatically after therapy was discontinued, suggesting that more prolonged periods of therapy are necessary to eradicate systemic infection.

PURPOSE: Estrogen replacement therapy is believed by many physicians to cause thrombophlebitis and to be contraindicated in women at risk for this disease. However, clinical data supporting this assumption are scant, and further investigation is required. PATIENTS AND METHODS: We tested the estrogen-thrombophlebitis association in a case-control study. Charts of all consecutive women aged 45 years or older with a primary or secondary discharge diagnosis of thrombophlebitis, venous thrombosis, or pulmonary embolism were reviewed; 121 cases and 236 controls matched for age, year of admission, admitting service, and socioeconomic status were obtained. Hormone use and nonuse were validated in a subset of randomly selected women. RESULTS: Cases and controls, whose average age was 65 years, did not differ significantly on matching variables or on current use of exogenous estrogen (5.1% of cases versus 6.3% of controls). Other analyses that variously excluded women with a past history of thrombosis, women less than 50 years of age, women with thrombosis occurring after admission, and women whose estrogen use was indeterminate also did not support an increased risk of thrombotic disease. Adjustment for the presence of independent thrombotic risk factors did not alter the odds ratio for estrogen use. CONCLUSION: This case-control study of older women, unselected for other thrombotic risk factors, does not support the commonly held assumption that replacement estrogen increases the risk of venous thrombosis.

* Objective: To compare pyrimethamine plus clindamycin (PC) to pyrimethamine plus sulfadiazine (PS) as a treatment for toxoplasmic encephalitis (TE) in patients with the acquired immunodeficiency syndrome (AIDS). * Design: Randomized, unblinded phase II, multicenter trial with provision for crossover for failure or intolerance of the assigned regimen. * Setting: University hospitals. * Patients: Eighty-four patients with presumptive TE were entered. Thirteen were excluded when they were found to have another diagnosis, and 12 were excluded because they did not meet entry criteria. The baseline characteristics in the remaining 26 patients randomized to PC and 33 randomized to PS were comparable. * Interventions: Patients were treated for 6 weeks with pyrimethamine and folinic acid plus either sulfadiazine or clindamycin. Clindamycin was given intravenously during the first 3 weeks. * Measurements and Main Results: There was a trend toward greater survival in patients randomized to PS (hazard ratio, 3.25; 95% Cl, 0.63 to 16.8; P = 0.13), but most study deaths were not directly related to TE. In contrast, patients randomized to PC appeared more likely to achieve complete clinical (odds ratio, 0.67; Cl, 0.2 to 1.97; P > 0.2) and radiologic responses (odds ratio, 0.28; Cl, 0.08 to 0.96; P = 0.02). Multivariate analysis revealed drug effects to be largely independent of other variables. Similar efficacy of the treatments was also suggested by a hazard analysis of resolution of abnormal mental status, fever, and headache. Skin rash was the most common adverse event in both treatment arms. Because of toxicity, six patients randomized to PC and 11 patients randomized to PS had to switch to the alternate treatment, but only three were unable to complete therapy after crossover. * Conclusions: The results of several end points of efficacy, taken together, suggest that the relative efficacy of PC approximately equals that of PS. PC appears to be an acceptable alternative in patients unable to tolerate PS.

The human immunodeficiency virus (HIV, the virus that causes AIDS) attacks and destroys the immune system, making individuals with AIDS very susceptible to other types of infection. Mycobacterium avium (M. avium) is a common bacterial cause of lung infection in patients with AIDS. Once M. avium infects the lungs it can spread (disseminate) to other parts of the body and cause M. avium complex infection (MAC). Many studies have reported that MAC reduces the survival time of patients with AIDS, but the validity of these studies has been challenged. In an attempt to gain a better understanding of the role that MAC plays in altering the survival time of AIDS patients, the medical records were reviewed of 137 AIDS patients attending the San Francisco General Hospital between 1983 and 1986. Thirty-four of the patients were diagnosed with lung infections caused by M. avium. In 22 of the 34 cases, the infection had spread to other parts of the body. When the infection spread to other parts of the body, the survival time of the patient was indeed shortened. It is concluded that a lung infection with M. avium predicts the development of disseminated MAC, and disseminated MAC reduces the survival time of patients with AIDS. (Consumer Summary produced by Reliance Medical Information, Inc.)

The human immunodeficiency virus is the virus that causes AIDS. The virus attacks and destroys the cells of the immune system (the body's natural defense system for fighting infection), and therefore patients with AIDS are at greater risk for developing life-threatening infections. Pneumonia caused by an infection with Pneumocystis carinii is one of the more common complications in patients with AIDS and it has been reported to be the cause of death in many cases. Many patients with AIDS develop simultaneous infections with several different microorganisms, and infection with Cytomegalovirus (CMV) is common in these patients. Several studies have tried to determine whether the rates of disease and death are greater in AIDS patients who have infections with both P. carinii and CMV than in those who have an infection with P. carinii alone. Two of these studies reported that infection with CMV did not increase mortality in AIDS patients with P. carinii pneumonia, while three other studies reported that patients with both CMV and P. carinii infection had a poorer outcome. To investigate this issue further, the effect of CMV infection on mortality and morbidity was determined in 111 AIDS patients with P. carinii pneumonia. Fifty-four of the patients had CMV infection and P. carinii pneumonia and 57 had P. carinii pneumonia without CMV infection. The length of hospitalization, long-term survival and death rate were the same for both groups of patients. It is concluded that CMV infection does not increase morbidity or mortality in AIDS patients with P. carinii pneumonia. These findings do not support the use of antiviral drugs for treating CMV infections in AIDS patients with P. carinii pneumonia. (Consumer Summary produced by Reliance Medical Information, Inc.)

Hairy leukoplakia (a viral infection causing hairy white patches on the tongue and mucous membranes of the mouth) is often seen in those infected with HIV, the human immunodeficiency virus. Hairy leukoplakia often occurs early in the course of HIV infection, and may be the first sign of the infection. Studies estimate that individuals who test positive for HIV antibodies will progress to full-blown AIDS within 18 to 36 months of showing signs of hairy leukoplakia. The time lag varies widely, however, and studies performed so far have had relatively small numbers of subjects. To determine what clinical factors might speed the progression from HIV infection to AIDS in individuals who have hairy leukoplakia, those who progressed to AIDS rapidly were compared with those who did not progress within 1,000 days. There were 28 patients in the group that progressed rapidly and 27 in the group that did not. Subjects underwent medical examination and provided information from which a history was constructed. Risk factors emerged upon statistical analysis and fell into two broad categories: sexual practices which correlated with how early during the AIDS epidemic patients were likely to have been infected, and factors reflecting the strength of the immune system. Regarding the latter, patients with a history of hepatitis B or syphilis had a four- and three-fold increase, respectively, in the likelihood that they would progress rapidly from HIV infection to AIDS. Of the skin tests performed, inability to show an immune response to Candida (yeast) was found in all 17 patients tested in the early progression group and in only two of 12 tested in the other group. Therefore, infection early in the AIDS epidemic, history of certain sexually transmitted diseases, and poor immune response to a skin test for Candida seem to be predictive of a relatively quick progression from HIV infection to AIDS in individuals with hairy leukoplakia. (Consumer Summary produced by Reliance Medical Information, Inc.)

Patients with acquired immunodeficiency syndrome (AIDS) are susceptible to a form of pneumonia resulting from infection with the organism Pneumocystis carinii. Treatment with intravenous pentamidine has been successful and a study was conducted comparing the effectiveness of reduced-dose pentamidine given intravenously and pentamidine by inhalation in these patients. Seventeen patients received aerosolized pentamidine and 22 patients received intravenous pentamidine. Although inhaled pentamidine is less toxic than the same drug given intravenously, treatment failures, return of symptoms, and a relapse rate of 24 percent occurred, leading to early termination of the study. Previously reported success rates have been variable, with a low of less than 20 percent and a high of 80 percent. The failure and relapse rates in this study with aerosolized pentamidine were considered unacceptably high; reduced-dose pentamidine, however, is considered an effective treatment for mild to moderate P. carinii pneumonia in AIDS patients. The rate of major toxicities from lower doses of intravenous therapy in this study was reduced 14 percent and thus low dose pentamidine is considered acceptable therapy. (Consumer Summary produced by Reliance Medical Information, Inc.)

A Prospective Study Samuel A. Bozzette, M.D.; David Feigal, M.D., M.P.H.; Joseph Chiu, M.D.; Daniel Gluckstein, M.D.; Carol Kemper, M.D.; Fred Sattler, M.D.; and the California Collaborative Treatment Group Survival [...]

Clinical Pharmacology & Therapeutics (2001) 69, 387–399; doi: 10.1067/mcp.2001.115455

To learn about the status of junior faculty in the specialty of pulmonary diseases and about their attitudes concerning their future in academic medicine.

The efficacy and toxicity of pentamidine inhaled once a month to prevent Pneumocystis cariniipneumonia (PCP) was investigated in 102 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). The cohort was compared with historical controls after a mean duration of prophylaxis of 6·38 months. 86% and 15% of the patients had AIDS or ARC, respectively. 50% of patients had had one previous episode of PCP, 9 % had had two episodes, and 3% had had three. 11 patients acquired PCP. Among these 51 patients with one prior episode of PCP, the PCP-free survival after 3·03, 4·7, and 6·38 months of prophylaxis was 98%, 92%, and 82%, respectively. Compared with those for historical controls, the data suggest that inhaled pentamidine can delay relapse by 6 months and reduce the rate of relapse by 50%. PCP acquired while patients were inhaling pentamidine prophylactically was mild and had a case-fatality rate of only 9%. Further investigation of the prophylactic value of inhaled pentamidine is warranted.

Abstract: Objective: To determine the reliability and validity of various physical diagnostic techniques (including three methods of palpation and three methods of percussion) in detecting ultrasonographically identified splenomegaly. Design: Prospective, double-blind study. Setting: University hospital. Patients: Twenty-seven hospitalized male patients with suspected human immunodeficiency virus (HIV) infection. Interventions: Three methods of palpation (bimanual, ballottement, and palpation from above) and three methods of percussion (as described by Nixon, Castell, and Barkun et al.) were performed on each patient by eight examiners. Splenic ultrasonography was performed within 96 hours of admission. Measurements and main results: The prevalence of splenomegaly by ultrasonography (defined as a spleen ≥ 13 cm on the longitudinal scan) in this population was 33.3%. The sensitivity and specificity of each method of palpation and percussion varied by examiner. The ranges of sensitivity across examiners for the three methods of palpation and the three methods of percussion were 0%–64.3% and 7.7%–75%, respectively. The ranges of specificity across examiners for the three methods of palpation and the three methods of percussion were 50%–100% and 60%–100%, respectively. Likelihood ratios pooled across observers revealed that for palpation, palpation from above, and percussion, Castell’s method had the highest likelihood ratios [LR=2.66 and 1.97, respectively; 95% CI=1.52–4.64 and 1.22–3.19, respectively]. A combination of tests (either palpation or percussion) increased the diagnostic accuracy. Conclusion: Physical diagnostic techniques for the detection of splenomegaly are relatively insensitive but specific. In this study there was high interobserver variability, which did not appear to be associated to the level of experience. Combining tests increases diagnostic accuracy.

Men and women with isolated systolic hypertension who were at least 60 years of age were treated for 1 year with chlorthalidone (25–50mg daily) or matching placebo as the step I drug. Most patients reached goal blood pressure without requiring a step II drug. The blood pressure response was similar in all age, sex and race subgroups, with an overall difference between the randomised groups of 17mm Hg for systolic blood pressure (p<0.001) and 6mm Hg for diastolic blood pressure (p<0.001). The only common adverse effects were asymptomatic changes in the serum concentrations of potassium (0.5 mmol/L lower in the chlorthalidone group, p<0.001), uric acid (0.9 mg/dl higher, p<0.001), and creatinine (0.08 mg/dl higher, p=0.02. Compliance was good, and more than 80% of participants were still taking the study medications at the end of the year. Les hommes et les femmes porteurs d’une hypertension systolique isolée, âgés au moins de 60 ans, ont été traités, en première intention, pendant 1 an avec du chlorthalidone (25–50 mg par jour) ou par le traitement placebo apparié. La plupart des malades ont atteint la pression sanguine recherchée sans qu’il soit nécessaire de passer au degré II du traitement médicamenteux. La réponse de la pression sanguine a été similaire dans tous les sous-groupes âge, sexe et race, avec une différence extrême entre les groupes tirés au sort de 17 mmHg pour la pression systolique (p<0.001) et 6 mmHg pour la pression diastolique (p<0.001). Les effets indésirables les plus fréquents ont été des changements asymptomatiques dans les concentrations sériques de potassium (moins 0,5 mmol/l dans le groupe chlorthalidone, (p<0.001), d’acide urique (plus 0,9 mg/dl, p<0.001), et de créatinine (plus 0,08 mg/dl, p=0.02). L’adhésion au traitement a été bonne, et plus de 80% des participants continuaient de prendre leurs médicaments à la fin de l’année de traitement. Männer und Frauen mit einer isolierten systolischen Hypertonie, die mindestens 60 Jahre alt waren, wurden über ein Jahr mit Chlorthalidon (25–50 mg täglich) oder gleichartigem Placebo als Pharmaka der ersten Stufe behandelt. Die meisten Patienten erreichten den erwünschten Blutdruck, ohne daβ ein Medikament der zweiten Stufe erforderlich war. Die Blutdruck-Reaktion war in allen Alters-, Geschlechts-und Rassen-Untergruppen ähnlich mit einem Gesamtunterschied zwischen den randomisierten Gruppen von 17 mmHg für den systolischen Blutdruck (p<0,001) und 6 mmHg für den diastolischen Blutdruck (p<0,001). Die einzige gemeinsame Nebenwirkung bestand in einer asymptomatischen Veränderung des Kalium in den Serumkonzentrationen (0,5 mmol/L niedriger in der Chlorthalidon-Gruppe, p<0,001), Harnsäure (0,9 mg/dl höher, p<0,001) und Kreatinin (0,08 mg/dl höher, p=0,02 . Bei einer guten Compliance nahmen 80% der Teilnehmer die Medikationen der Untersuchung noch am Ende des Jahres. Hombres y mujeres con hipertensión sistólica aislada, que tenían por lo menos 60 años de edad, se han tratado durante 1 año con clortalidona (25–50 mg diarios), o placebo de análogo aspecto, como fármaco de etapa I. La mayoría de los pacientes alcanzaron la presión deseada sin necesitar medicamento de etapa II. La respuesta tensional fue semejante en todos los grupos de edad, sexo y raza con una diferencia total entre los grupos aleatorizados de 17 mm Hg para la presion sistólica (p<0,001) y de 6 mm Hg para la diastólica (p<0,001). Los únicos efectos adversos de manifestación frecuente fueron modificaciones asintomáticas de las concentraciones séricas de potasio (0,5 mmol/l menos en el grupo clortalidona, p<0,001), de ácido úrico (0,9 mg/dl mas, p<0,001) y de cretinina (0,08 mg/dl más, p=0,02). La aceptación fue buena y más del 80% de participantes todavía estaban tomando las medicaciones en estudio al final del año. Homens e mulheres com hipertensão sistólica isolada e com idade mínima de 60 anos foram tratados por um ano com clortalidona (25 a 50 mg por dia) ou placebo equivalente como drogas de primeira escolha. A maioria dos pacientes atingiu o nível de pressão sanguínea objetivado sem recorrerem a outras drogas. A reação da pressão sanguínea foi semelhante em todos os subgrupos, fossem por idade, sexo ou raça, com uma diferença global entre os grupos selecionados de 17 mmHg para a pressão sistólica (p<0,001) e 6 mmHg para a pressão diastólica (p<0,001). Os únicos efeitos adversos comuns a todos foram mudanças assintomáticas nas concentrações de potássio no soro (0,5 mmol/L abaixo, no grupo com clortalidona, cortalidona, p<0,001), no ácido ùrico (0,9 mg/dl acima, p<0,001) e na creatinina (0,08 mg/dl acima, p=0,02). O indice de observância ao tratamento foi bom, sendo que mais de 80% dos participantes ainda estavam a tomar os medicamentos empregados durante a experiência ao final do ano. Soggetti di entrambi i sessi di almeno 60 anni con ipertensione sistolica isolata furono trattati per un anno con clortalidone (25–50 mg al giorno) o placebo, come farmaco di primo livello. La maggior parte dei pazienti normalizzarono la loro pressione arteriosa senza richiedere un farmaco di secondo livello. La risposta pressoria fu simile in tutti i sottogruppi di età, sesso e razza, con una differenza totale tra i gruppi randomizzati di 17 mm Hg per la pressione sistolica (p<0.001) e 6 mm Hg per la diastolica (p<0.001). I soli comuni effetti indesiderati furono modificazioni asintomatiche nette concentrazioni sieriche di potassio (di 0,5 mmol/1 inferiore nel gruppo trattato con clortalidone, p< 0.001), acido urico (di 0.9 mg/dl più alto, p<0.001) e creatinina (di 0.08 mg/dl maggiore, p<0.02). La compliance fu buona e più dell’80% dei partecipanti allo studio era ancora in trattamento alla fine dell’anno.

Abstract: OBJECTIVE: To compare the management of mild diastolic hypertension (90 to 104 mm Hg) using a nonpharmacologic intervention with that using propranolol or placebo. DESIGN: Randomized, placebo-controlled trial with a 22 factorial design. SETTING: University-based ambulatory care center. PARTICIPANTS: Two hundred seven men and 105 women, 22 to 59 years of age, 73% white, who had mild diastolic hypertension untreated for at least eight weeks. INTERVENTIONS: 1) a multicomponent lifestyle modification intervention (lifestyle focus group, or LFG) administered in eight weekly meetings+placebo, 2) LFG+propranolol, 3) propranolol alone, and 4) placebo alone, followed for 12 months. MEASUREMENTS: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and self-reported adverse effects at each of nine follow-up visits; fasting total cholesterol, triglycerides, and glucose at baseline and 12 months; 24-hour urine sodium (Na+) and potassium (K+), three-day food records and physical activity questionnaire at three and 12 months; and a quality of life questionnaire at 12 months. MAIN RESULTS: The mean decreases in DBP at 12 months were: 8.5 mm Hg in the LFG+propranolol group; 7.7 mm Hg in the propranolol-only group; 5.9 mm Hg in the placebo-only group; and 5.4 mm Hg in the LFG+placebo group. Repeated-measures analysis of covariance showed that level of baseline DBP (p<0.0001), time of follow-up (p<0.0001), and propranolol use (p<0.0001) were significantly associated with a decrease in DBP at 12 months. Despite reductions in urinary Na+ (−35 mEq; 95% CI=−50, −19), dietary Na+ (−521 mg; 95% CI=−710, −332), total calories ingested (−238; 95% CI=−335, −140), and weight (−1.4 lb; 95% CI=−3.7, +0.8), and significant increases in dietary K+ (+294 mg; 95% CI=+107, +480) and in mets-minutes of exercise (+43; 95% CI=+20, +67) at three months, assignment to the LFG intervention had no effect on DBP at three or 12 months. The subjects assigned to take propranolol more frequently reported fatigue during ordinary activities, sleep disturbance, decrease in sexual activity, and depressed feelings, when compared with the subjects taking placebo, but the numbers of study withdrawals did not differ by drug assignment. No significant difference in total cholesterol and glucose levels was observed by group assignment. Triglycerides increased significantly in the subjects assigned to propranolol (mean difference=+20 mg/dL; 95% CI of difference +1.5, +39). There was no difference in the responses to 21 quality of life items between the subjects assigned to propranolol and those assigned to placebo. CONCLUSIONS: This multicomponent lifestyle modification intervention was unable to promote persistent behavior changes and thus was inferior to propranolol therapy for the treatment for mild diastolic hypertension. Future research should focus on single modifiable factors to lower blood pressure.

• We assessed the effect of antiviral therapy on serum human immunodeficiency virus core antigen (HIV-Ag) levels in patients enrolled in the phase II trial on zidovudine for acquired immunodeficiency syndrome (AIDS) and AIDS—related complex. Human immunodeficiency virus core antigen was detected in 45% of subjects at entry (59% with AIDS and 37% of patients with AIDS—related complex). Median HIV-Ag levels in zidovudine-treated subjects fell from 111 pg/mL at entry to 46 pg/mL at four weeks, while levels in placebo recipients did not change significantly. Decline in HIV-Ag in zidovudine recipients was sustained through 16 weeks of treatment and was significantly different from the placebo group. Anti—p24 antibody levels did not change in either group. We conclude that in patients with HIV-antigenemia changes in HIV-Ag level are an important marker of anti—retroviral activity.(Arch Intern Med 1988;148:2151-2153)

Of 760 AIDS patients seen at San Francisco General Hospital in 1986, 5.7 per cent had retinitis and 2.2 per cent had gastrointestinal disease caused by cytomegalovirus. We reviewed the records of 44 patients treated with ganciclovir for culture-confirmed cytomegalovirus retinal (31 patients) or gastrointestinal disease (17 patients) or both (four patients) in 1986. Retinitis stabilized or improved during initial treatment with ganciclovir in 22 of 27 (81.5 per cent) patients. Following a median 10-day induction course, 16 patients with retinitis continued to have serial ophthalmologic assessments: eight patients were maintained on treatment and eight had maintenance treatment deferred. Before treatment, the two groups were comparable in age, Karnofsky scores, hematologic assessment, visual acuity, and history with respect to Pneumocystic carinii pneumonia. Retinitis did not progress for a median 53.8 days in the immediate maintenance group compared to 18.8 days for the deferred maintenance group (p=0.01). In 17 patients with CMV gastrointestinal disease, nine of 14 (64 per cent) had resolution of pain and eight of 11(73 per cent) had resolution of diarrhea when treated initially with ganciclovir. In both retinitis and gastrointestinal disease patients, ganciclovir decreased recovery of CMV from urine and blood markedly. Ganciclovir also caused a decrease in mean absolute neutrophil counts to about half of baseline values; decreases in mean platelet count and hemoglobin were also noted but were less than 25 per cent. Neutropenia severe enough to require dose adjustment (<800 cells/μl) occured in 31 per cent of patients receiving maintenance ganciclovir.