Efficacy and safety of caspofungin therapy in elderly patients with proven or suspected invasive fungal infections.

Invasive fungal infections (IFIs) are serious complications in elderly adults. Caspofungin may provide a useful therapeutic option for elderly patients with or at high risk for IFIs. We retrospectively compared efficacy and safety outcomes in elderly (> or = 65 years of age) and non-elderly patients in three clinical trials of caspofungin: a double-blind, randomized trial versus amphotericin B for documented invasive candidiasis (IC); an open-label, non-comparative study of definite or probable invasive aspergillosis (IA); and a double-blind, randomized trial versus liposomal amphotericin B as empirical therapy (ET) in febrile neutropenic patients. A total of 159 elderly patients with a median age of 71 years (range, 65-84) received caspofungin in these studies. The median duration of caspofungin therapy was 12 days for IC and ET, and 28 days for IA. Point estimates for the favorable response rates to caspofungin were numerically higher in elderly versus non-elderly patients with IC (83% vs. 68%) or IA (64% vs. 44%) and were similar in patients receiving ET (36% vs. 34%). Adverse events related to caspofungin occurred in generally similar proportions of elderly versus non-elderly patients with IC (clinical, 33% vs. 27%; laboratory, 17% vs. 29%), with IA (clinical, 7% vs. 13%; laboratory, 13% vs. 14%), or receiving ET (clinical, 47% vs. 47%; laboratory, 24% vs. 22%). Nephrotoxicity and infusion-related toxicity developed in comparable proportions of elderly and non-elderly caspofungin recipients in all three studies. In this post-hoc analysis, caspofungin appeared to be as efficacious and well tolerated in elderly patients as in non-elderly patients.

Management of complicated appendicitis and comparison of outcome with other primary sites of intra-abdominal infection: results of a trial comparing ertapenem and piperacillin-tazobactam.

A post-hoc analysis of data from a trial of complicated intra-abdominal infection was performed to compare the demographic and disease characteristics of patients with complicated appendicitis to those whose primary infection involved other intra-abdominal sites, assess the impact of site of primary infection on outcome, and compare the efficacy and safety of ertapenem 1 g daily with piperacillin-tazobactam 3.375 g every 6 h for treatment of complicated appendicitis. Compared with patients who had primary infection of the colon or another site in the abdomen, patients with complicated appendicitis were younger, had less severe disease (based on lower APACHE II score and lower proportion with generalized peritonitis), and were less likely to be managed by percutaneous drainage of an abscess or to have a postoperative infection. Patients with complicated appendicitis were more likely to have a favorable outcome than were patients with infection of the colon (OR, 3.02; 95% CI, [1.54-5.901; P = .001). At the test-of-cure assessment, 109/123 (88.6%) microbiologically evaluable patients with complicated appendicitis who received ertapenem and 102/113 (90.3%) who received piperacillin-tazobactam had a favorable combined clinical and microbiologic outcome. The frequency and severity of drug-related adverse events were similar in the two treatment groups.

Residual human immunodeficiency virus (HIV) Type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years.

Residual viral replication persists in a significant proportion of human immunodeficiency virus (HIV)-infected patients receiving potent antiretroviral therapy. To determine the source of this virus, levels of HIV RNA and DNA from lymphoid tissues and levels of viral RNA in serum, cerebrospinal fluid (CSF), and genital secretions in 28 patients treated for < or =2.5 years with indinavir, zidovudine, and lamivudine were examined. Both HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF samples after 2 years of treatment. HIV envelope sequence data from plasma and lymph nodes from 4 patients demonstrated sequence divergence, which suggests varying degrees of residual viral replication in 3 and absence in 1 patient. In patients receiving potent antiretroviral therapy, the greatest virus burden may continue to be in lymphoid tissues rather than in central nervous system or genitourinary compartments.

3-year suppression of HIV viremia with indinavir, zidovudine, and lamivudine.

BACKGROUND: Antiretroviral regimens containing HIV protease inhibitors suppress viremia in HIV-infected patients, but the durability of this effect is not known. OBJECTIVE: To describe the 3-year follow-up of patients randomly assigned to receive indinavir, zidovudine, and lamivudine in an ongoing clinical trial. DESIGN: Open-label extension of a randomized, double-blind study. SETTING: Four clinical research units. PATIENTS: 33 HIV-infected, zidovudine-experienced patients with serum HIV RNA levels of at least 20,000 copies/mL and CD4 counts ranging from 50 to 400 cells/mm3. INTERVENTION: Indinavir, zidovudine, and lamivudine. MEASUREMENTS: Safety assessments, HIV RNA levels, CD4 cell counts, and genotypic analyses. RESULTS: After 3 years of follow-up, 21 of 31 contributing patients (68% [95% CI, 49% to 83%]) had serum viral load levels less than 500 copies/mL. Twenty of 31 (65% [CI, 45% to 80%]) had levels less than 50 copies/mL. The median increase in CD4 count from baseline was 230 cells/mm3 (interquartile range, 150 to 316 cells/mm3). Nephrolithiasis occurred in 12 of 33 patients (36%). CONCLUSION: A three-drug regimen of indinavir, zidovudine, and lamivudine suppressed viremia in two thirds of patients for at least 3 years.

A randomized, controlled trial of indinavir, zidovudine, and lamivudine in adults with advanced human immunodeficiency virus type 1 infection and prior antiretroviral therapy.

A randomized, double-blind, multicenter study of indinavir, zidovudine, and lamivudine was conducted in 320 adults with human immunodeficiency virus type 1 (HIV-1) infection,

Modeling the long-term outcomes and costs of HIV antiretroviral therapy using HIV RNA levels: application to a clinical trial.

A model was developed to gain insight into the potential clinical and economic impact of antiretroviral therapy for HIV-infected patients. Observed HIV RNA levels and CD4 cell counts are used in the model to estimate the probability that an individual progresses from asymptomatic infection to the first AIDS-defining illness and death and to estimate the total net cost of care and long-term cost-effectiveness of antiretroviral therapy. The model was applied to patients in a clinical trial (Merck protocol 035) that compared the surrogate marker response to triple therapy with indinavir (IDV; 800 mg every 8 hr) plus zidovudine (ZDV; 200 mg every 8 hr) plus lamivudine (3TC; 150 mg twice a day) to double therapy with ZDV+3TC. The model projected that for an individual without AIDS who received triple therapy the progression to AIDS and death would be delayed more than for a patient who received double therapy with ZDV+3TC if no other treatment options were offered. Because of this delay in disease progression, the total discounted cost over the initial 5-year period was projected to be $5100 lower for patients who received triple therapy compared with double therapy if suppression with triple therapy lasts up to 3 years. If suppression with triple therapy lasts up to 5 years, costs were projected to be higher with the triple combination, but 81% of the cost is offset by lower disease costs as a result of fewer patients progressing to AIDS. Over 20 years, total discounted cost was projected to be higher for the triple-therapy regimen primarily because of a longer estimated survival time. At 20 years, the incremental cost per life-year gained by adding IDV to a ZDV+3TC regimen was estimated at $13,229, which is well within the range of other widely accepted medical interventions.

Factors influencing the emergence of resistance to indinavir: role of virologic, immunologic, and pharmacologic variables.

A major problem with the use of human immunodeficiency virus type 1 (HIV-1) protease inhibitors as monotherapy has been an unacceptably high rate of emergence of resistance. To examine possible influences on the time to emergence of resistance, 24-week data were examined from five studies in which indinavir had been administered as monotherapy or as a component of combination therapy. Monotherapy data indicated a correlation between the level of HIV-1 RNA achieved and the risk of emergence of resistance: the lower the level, the lower the risk. When combination and monotherapy regimens were compared, the group receiving indinavir + lamivudine + zidovudine had a significantly lower risk of resistance, even after adjusting for the minimum HIV-1 RNA level achieved. The findings indicate that if at all possible, HIV-1-infected patients should receive combination chemotherapy to minimize the emergence of resistance to the protease inhibitor portion of the regimen. The goal of therapy should be to decrease the HIV-1 RNA load to a less-than-detectable level.

Simultaneous vs sequential initiation of therapy with indinavir, zidovudine, and lamivudine for HIV-1 infection: 100-week follow-up.

CONTEXT: Combination antiretroviral therapy can markedly suppress human immunodeficiency virus (HIV) replication but the duration of HIV suppression varies among patients. OBJECTIVE: To compare the antiretroviral effect of a 3-drug regimen started simultaneously or sequentially in patients with HIV infection. DESIGN: A multicenter, randomized, double-blind study, modified after at least 24 weeks of blinded therapy to provide open-label 3-drug therapy with follow-up through 100 weeks. SETTING: Four clinical research units PATIENTS: Ninety-seven patients with HIV infection who had taken zidovudine for at least 6 months with serum HIV RNA level of at least 20000 copies/mL and CD4 cell count of 0.05 to 0.40 x 10(9)/L. INTERVENTIONS: Patients were initially randomized to receive 1 of 3 antiretroviral regimens: indinavir, 800 mg every 8 hours; zidovudine, 200 mg every 8 hours and lamivudine, 150 mg every 12 hours; or all 3 drugs. After at least 24 weeks of blinded therapy, all patients received open-label 3-drug therapy. MAIN OUTCOME MEASURES: Antiretroviral activity was assessed by changes in HIV RNA level and CD4 cell count from baseline. Data through 100 weeks were summarized. RESULTS: Simultaneous initiation of indinavir, zidovudine, and lamivudine suppressed HIV RNA in 78% (25/32) of contributing patients to less than 500 copies/mL and increased CD4 cell count to a median of 0.209 x 10(9)/L above baseline at 100 weeks. When these 3 drugs were initiated sequentially, only 30% to 45% of contributing patients (10 of 33 in the zidovudine-lamivudine group and 13 of 29 in the indinavir group, respectively) had a sustained reduction in HIV RNA to less than 500 copies/mL, and median CD4 cell count increased to 0.101 to 0.163 x 10(9)/L above baseline at 100 weeks. CONCLUSIONS: A 3-drug combination of indinavir, zidovudine, and lamivudine started simultaneously has durable antiretroviral activity for at least 2 years. Sequential initiation of the same 3 drugs is much less effective.

Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy.

BACKGROUND: The new protease inhibitors are potent inhibitors of the human immunodeficiency virus (HIV), and in combination with other antiretroviral drugs they may be able to cause profound and sustained suppression of HIV replication. METHODS: In this double-blind study, 97 HIV-infected patients who had received zidovudine treatment for at least 6 months and had 50 to 400 CD4 cells per cubic millimeter and at least 20,000 copies of HIV RNA per milliliter were randomly assigned to one of three treatments for up to 52 weeks: 800 mg of indinavir every eight hours; 200 mg of zidovudine every eight hours combined with 150 mg of lamivudine twice daily; or all three drugs. The patients were followed to monitor the occurrence of adverse events and changes in viral load and CD4 cell counts. RESULTS: The decrease in HIV RNA over the first 24 weeks was greater in the three-drug group than in the other groups (P<0.001 for each comparison). RNA levels decreased to less than 500 copies per milliliter at week 24 in 28 of 31 patients in the three-drug group (90 percent), 12 of 28 patients in the indinavir group (43 percent), and none of 30 patients in the zidovudine-lamivudine group. The increase in CD4 cell counts over the first 24 weeks was greater in the two groups receiving indinavir than in the zidovudine-lamivudine group (P< or =0.01 for each comparison). The changes in the viral load and the CD4 cell count persisted for up to 52 weeks. All the regimens were generally well tolerated. CONCLUSIONS: In most HIV-infected patients with prior antiretroviral therapy, the combination of indinavir, zidovudine, and lamivudine reduces levels of HIV RNA to less than 500 copies per milliliter for as long as one year.

An occupation based physical activity intervention program: improving fitness and decreasing obesity.

The purpose of this quasi-experimental study was to determine the effectiveness of an occupation based health and fitness program. Subjects were 1,504 police trainees (85% male, 15% female) with an ethnic distribution of 82% white, 16% African American, and 2% other. Data were collected at 25 sites across the state of North Carolina. The sites were randomly assigned to either the experimental group (implemented the intervention) or the control group (continued usual training). As compared with controls, subjects at the experimental sites improved significantly in cardiovascular fitness (aerobic power), general muscular strength (number of sit ups per minute), and flexibility, and lowered their body fat. The intervention required minimal equipment and was taught primarily by peers who received a 1 week training program. This occupational approach to improving health could be particularly useful in occupations with many workers who seldom engage in leisure time physical activity.

The impact of a preconceptional health promotion program on intendedness of pregnancy.

The objective for this study was to determine whether a brief preconceptional health promotion program for low-income women attending family planning clinics impacts on intendedness of pregnancy. In this prospective study, we examined data on 1378 women presenting for prenatal care at three local health departments. Each of the departments offers a standardized preconceptional health promotion program in its family planning clinics. Comparisons were undertaken for 456 women who had been exposed to the family planning preconception program, 309 women who had attended the family planning clinics but had not been exposed to the program, and 613 women who were unknown to the health department before beginning prenatal care. Women exposed to information on preconceptional health during routine family planning visits, the experimental group, had a 51.8% (p = 0.064) greater likelihood of identifying their pregnancies at intended than a group known to the local health departments' family planning programs but unexposed to the intervention. Furthermore, the experimental group had a 64.2% (p = 0.0009) greater likelihood of intendedness than a comparison group not known to the health departments before the initiation of prenatal care. Our study indicates that an introductory program of preconceptional health promotion which is targeted to women not planning a pregnancy in the immediate future is associated with a higher rate of intendedness in subsequent pregnancies. Expansion of similar preconceptional programs in family planning clinics may prove a useful approach for promoting intendedness of pregnancy in low-income women.

The effects of angiotensin II receptor blockade with losartan on systemic blood pressure and renal and extrarenal prostaglandin synthesis in women with essential hypertension.

The major antihypertensive effect of losartan, a nonpeptide angiotensin II antagonist, is thought to be due to inhibition of the pressor effects of angiotensin II. It is possible, however, that losartan alters the synthesis of vasodilator or vasoconstrictor prostaglandins (PG), thus contributing to its antihypertensive effect. Sixteen postmenopausal women with essential hypertension, with a mean age of 59 years and diastolic blood pressures of 95 to 115 mm Hg, were enrolled in a 12-week, single-blind study to determine the effects of losartan on blood pressure, renal and extrarenal PG production, plasma renin activity (PRA), plasma aldosterone, and routine biochemical parameters. The subjects received placebo during weeks 1 to 4, 50 mg losartan daily during weeks 5 to 8, and placebo during weeks 9 to 12. During the 4-week treatment period, there were no significant, sustained changes in renal or extrarenal synthesis of PGE2, PGI2, or thromboxane A2. Losartan significantly reduced systolic blood pressure from 155 +/- 11 mm Hg (mean +/- SD) to 139 +/- 13 mm Hg (P = .001) and diastolic blood pressure from 100 +/- 2 mm Hg to 87 +/- 5 mm Hg (P < .001) despite the fact that the majority of patients had low PRA. Plasma aldosterone concentration decreased from 9.7 +/- 6.5 ng/dL to 5.1 +/- 3.9 ng/dL (P = .002) and serum uric acid declined from 4.6 +/- 0.8 mg/dL to 4.2 +/- 0.8 mg/dL (P = .018) after 4 weeks of treatment with losartan. We conclude that 1) losartan decreases blood pressure in women with essential hypertension and low plasma renin activity; 2) the antihypertensive effect is not associated with sustained changes in renal or extrarenal PG production; and 3) losartan reduces plasma aldosterone and serum uric acid concentrations in patients with essential hypertension.

Migraine prevention with timolol. A double-blind crossover study.

One hundred seven patients (77 women and 30 men) with migraine headache were given prophylactic treatment with timolol maleate, 20 to 30 mg/day, or matching placebo during a 20-week, double-blind crossover study. Among the 94 patients who completed the study, timolol was significantly better than placebo in terms of decrease in frequency of headaches from baseline, numbers of patients who had a 50% reduction in headache frequency, global response, and patient preference. Overall global response rates were 65% with timolol compared with 40% with placebo. The severity and duration of headaches that occurred were unchanged. Few side effects were reported with either timolol or placebo. The study demonstrates that the beta-blocker timolol is a safe and effective treatment in patients with frequent migraine headaches.