Monthly antibiotic chemoprophylaxis and incidence of sexually transmitted infections and HIV-1 infection in Kenyan sex workers: a randomized controlled trial

Context  Sexually transmitted infections (STIs) are common in female sex workers (FSWs) and may enhance susceptibility to infection with human immunodeficiency virus type 1 (HIV-1). Objective  To examine regular antibiotic prophylaxis in FSWs as a strategy for reducing the incidence of bacterial STIs and HIV-1. Design, Setting, and Participants  Randomized, double-blind, placebo-controlled trial conducted between 1998-2002 among FSWs in an urban slum area of Nairobi, Kenya. Of 890 FSWs screened, 466 who were seronegative for HIV-1 infection were enrolled and randomly assigned to receive azithromycin (n = 230) or placebo (n = 236). Groups were well matched at baseline for sexual risk taking and STI rates. Intervention  Monthly oral administration of 1 g of azithromycin or identical placebo, as directly observed therapy. All participants were provided with free condoms, risk-reduction counseling, and STI case management. Main Outcome Measures  The primary study end point was incidence of HIV-1 infection. Secondary end points were the incidence of STIs due to Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, Treponema pallidum, and Haemophilus ducreyi, as well as bacterial vaginosis. Analysis of herpes simplex virus type 2 (HSV-2) infection was performed post hoc. Results  Seventy-three percent of participants (n = 341) were followed up for 2 or more years or until they reached an administrative trial end point. Incidence of HIV-1 did not differ between treatment and placebo groups (4% [19 cases per 473 person-years of follow-up] vs 3.2% [16 cases per 495 person-years of follow-up] rate ratio [RR], 1.2; 95% CI, 0.6-2.5). Incident HIV-1 infection was associated with preceding infection with N gonorrhoeae (rate ratio [RR], 4.9; 95% CI, 1.7-14.3) or C trachomatis (RR, 3.0; 95% CI, 1.1-8.9). There was a reduced incidence in the treatment group of infection with N gonorrhoeae (RR, 0.46; 95% CI, 0.31-0.68), C trachomatis (RR, 0.38; 95% CI, 0.26-0.57), and T vaginalis (RR, 0.56; 95% CI, 0.40-0.78). The seroprevalence of HSV-2 infection at enrollment was 72.7%, and HSV-2 infection at baseline was independently associated with HIV-1 acquisition (RR, 6.3; 95% CI, 1.5-27.1). Conclusions  Despite an association between bacterial STIs and acquisition of HIV-1 infection, the addition of monthly azithromycin prophylaxis to established HIV-1 risk reduction strategies substantially reduced the incidence of STIs but did not reduce the incidence of HIV-1. Prevalent HSV-2 infection may have been an important cofactor in acquisition of HIV-1.      

Role of Seroconversion in Confirming Cure of Helicobacter pylori Infection

Context.— The role of serologic testing to confirm cure of Helicobacter pylori infection after antimicrobial therapy is not completely defined. Objective.— To determine the utility of serologic testing in confirming cure of H pylori infection more than 1 year after therapy. Design.— A prospective, before-after interventional trial. Setting.— An outpatient clinical research laboratory in an academic, urban Veterans Affairs medical center. Participants.— Twenty-three otherwise healthy men and women with active H pylori infection demonstrated by gastric biopsy and with positive H pylori serologic findings. Intervention.— A 14-day course of bismuth, tetracycline, and metronidazole. Main Outcome Measures.— Determination of IgG serum antibodies to H pylori at baseline, 1 month, 3 months, and approximately 18 months after completion of therapy compared with serial gastric mucosal biopsy specimens with stains for H pylori and for histologic examination as the criterion standard. Results.— Fifteen (65%) of 23 subjects were cured of their H pylori infection as assessed by gastric biopsy, with elimination of gastritis; median antibody levels declined from 92.5 U/mL at baseline to undetectable levels at 18 months. The other 8 subjects (35%) were not cured and had persistent gastritis at 18 months; median antibody levels declined from 130.6 U/mL at baseline to 89.7 U/mL at 18 months. Sensitivity and specificity of seroconversion (from a positive to negative test result) in detecting cure of H pylori infection were 60% and 100%, respectively. Conclusion.— Undetectable antibody levels beyond the first year of therapy accurately confirm cure of H pylori infection in initially seropositive healthy subjects, with reasonable sensitivity.      

Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial

Context  Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated. Objective  To test the efficacy and safety of a well-characterized H perforatum extract (LI-160) in major depressive disorder. Design and Setting  Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States. Participants  Adult outpatients (n = 340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20. Interventions  Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks. Main Outcome Measures  Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores. Results  On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was –9.20 (0.67) (95% confidence interval [CI], –10.51 to –7.89) for placebo vs –8.68 (0.68) (95% CI, –10.01 to –7.35) for H perforatum (P = .59) and –10.53 (0.72) (95% CI, –11.94 to –9.12) for sertraline (P = .18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum–treated patients (P = .21) and 24.8% of sertraline-treated patients (P = .26). Sertraline was better than placebo on the CGI improvement scale (P = .02), which was a secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo. Conclusion  This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low assay sensitivity of the trial, but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy.      

Hypericum perforatum (St John's wort) for attention-deficit/hyperactivity disorder in children and adolescents: a randomized controlled trial

Wendy Weber, ND, PhD, MPH; Ann Vander Stoep, PhD; Rachelle L. McCarty, ND, MPH; Noel S. Weiss, MD, DrPH; Joseph Biederman, MD; Jon McClellan, MD

JAMA. 2008;299(22):2633-2641.

Context  Stimulant medication can effectively treat 60% to 70% of youth with attention-deficit/hyperactivity disorder (ADHD). Yet many parents seek alternative therapies, and Hypericum perforatum (St John's wort) is 1 of the top 3 botanicals used.

Objective  To determine the efficacy and safety of H perforatum for the treatment of ADHD in children.

Design, Setting, and Participants  Randomized, double-blind, placebo-controlled trial conducted between March 2005 and August 2006 at Bastyr University, Kenmore, Washington, among a volunteer sample of 54 children aged 6 to 17 years who met Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for ADHD by structured interview.

Intervention  After a placebo run-in phase of 1 week, participants were randomly assigned to receive 300 mg of H perforatum standardized to 0.3% hypericin (n = 27) or a matched placebo (n = 27) 3 times daily for 8 weeks. Other medications for ADHD were not allowed during the trial.

Main Outcome Measures  Performance on the ADHD Rating Scale–IV (range, 0-54) and Clinical Global Impression Improvement Scale (range, 0-7), and adverse events.

Results  One patient in the placebo group withdrew because of an adverse event. No significant difference was found in the change in ADHD Rating Scale–IV scores from baseline to week 8 between the treatment and placebo groups: inattentiveness improved 2.6 points (95% confidence interval [CI], –4.6 to –0.6 points) with H perforatum vs 3.2 points (95% CI, –5.7 to –0.8 points) with placebo (P = .68) and hyperactivity improved 1.8 points (95% CI, –3.7 to 0.1 points) with H perforatum vs 2.0 points (95% CI, –4.1 to 0.1 points) with placebo (P = .89). There was also no significant difference between the 2 groups in the percentage of participants who met criteria for improvement (score 2) on the Clinical Global Impression Improvement Scale (H perforatum, 44.4%; 95% CI, 25.5%-64.7% vs placebo, 51.9%; 95% CI, 31.9%-71.3%; P = .59). No difference between groups was found in the number of participants who experienced adverse effects during the study period (H perforatum, 40.7%; 95% CI, 22.4%-61.2% vs placebo, 44.4%; 95% CI, 25.5%-64.7%; P = .78).

Conclusion  In this study, use of H perforatum for treatment of ADHD over the course of 8 weeks did not improve symptoms.

Trial Registration  clinicaltrials.gov Identifier: NCT00100295

     

Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial

Context  Basic research and observational evidence as well as results from trials of colon polyp recurrence suggest a role for aspirin in the chemoprevention of cancer. Objective  To examine the effect of aspirin on the risk of cancer among healthy women. Design, Setting, and Participants  In the Women’s Health Study, a randomized 2 x 2 factorial trial of aspirin and vitamin E conducted between September 1992 and March 2004, 39 876 US women aged at least 45 years and initially without previous history of cancer, cardiovascular disease, or other major chronic illness were randomly assigned to receive either aspirin or aspirin placebo and followed up for an average of 10.1 years. Intervention  A dose of 100 mg of aspirin (n=19 934) or aspirin placebo (n=19 942) administered every other day. Main Outcome Measures  Confirmed newly diagnosed invasive cancer at any site, except for nonmelanoma skin cancer. Incidence of breast, colorectal, and lung cancer were secondary end points. Results  No effect of aspirin was observed on total cancer (n = 2865; relative risk [RR], 1.01; 95% confidence interval [CI], 0.94-1.08; P = .87), breast cancer (n = 1230; RR, 0.98; 95% CI, 0.87-1.09; P = .68), colorectal cancer (n = 269; RR, 0.97; 95% CI, 0.77-1.24; P = .83), or cancer of any other site, with the exception of lung cancer for which there was a trend toward reduction in risk (n = 205; RR, 0.78; 95% CI, 0.59-1.03; P = .08). There was also no reduction in cancer mortality either overall (n = 583; RR, 0.95; 95% CI, 0.81-1.11; P = .51) or by site, except for lung cancer mortality (n = 140; RR, 0.70; 95% CI, 0.50-0.99; P = .04). No evidence of differential effects of aspirin by follow-up time or interaction with vitamin E was found. Conclusions  Results from this large-scale, long-term trial suggest that alternate day use of low-dose aspirin (100 mg) for an average 10 years of treatment does not lower risk of total, breast, colorectal, or other site-specific cancers. A protective effect on lung cancer or a benefit of higher doses of aspirin cannot be ruled out.      

Ultralow-dose micronized 17beta-estradiol and bone density and bone metabolism in older women: a randomized controlled trial

Context  Estrogen therapy is known to prevent osteoporosis, but studies have shown that conventional doses increase adverse events. Whether lower doses, one quarter of standard treatment, prevent bone loss is not known. Objective  To examine the effect of 3 years of treatment with 0.25 mg/d of micronized 17-estradiol on bone mineral density (BMD) and bone turnover in healthy older postmenopausal women. Design, Setting, and Participants  Randomized, double-blind, placebo-controlled trial conducted from July 24, 1998, through June 14, 2002, at a university general clinical research center in the United States. Healthy, community-dwelling women (N = 167) who were older than 65 years at enrollment. Intervention  Dosage of 0.25 mg/d of micronized 17-estradiol (n = 83) or placebo (n = 84); all women who had not had a hysterectomy received 100 mg/d of oral micronized progesterone for 2-week periods every 6 months. Main Outcome Measures  The BMD of the hip, spine, wrist, and total body measured annually for 3 years. Serum and urine biochemical markers of bone resorption and formation and sex hormones were measured at baseline, 3 months, and during years 1 and 3 of treatment. Results  Mean BMD increased at all sites for participants taking low-dose estrogen (17-estradiol) compared with placebo (P<.001). Compared with participants receiving placebo, participants taking low-dose estrogen had BMD increases of 2.6% for the femoral neck; 3.6%, total hip; 2.8%, spine; and 1.2%, total body. Markers of bone turnover, N-telopeptides of type 1 collagen, and bone alkaline phosphatase decreased significantly (P<.001) in participants taking low-dose estrogen compared with placebo. Estradiol, estrone, and sex hormone–binding globulin levels increased in the estrogen-treated group compared with placebo. The adverse effect profile was similar; specifically, there were no statistically significant differences in breast tenderness, changes in endometrial thickness or pathological effects, or annual mammographic results between the 2 groups. The number of abnormal mammograms over 3 years was 15 for the low-dose estrogen group and 10 for the placebo group (8 occurred at baseline) (P = .26). There were no reports of breast cancer during the study. Conclusions  In older women, a dosage of 0.25 mg/d of 17-estradiol increased bone density of the hip, spine, and total body, and reduced bone turnover, with minimal adverse effects. Future studies evaluating the effect of low-dose estrogen on fractures are indicated.      

Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease

Context  Vaso-occlusion is central to the painful crises and acute and chronic organ damage in sickle cell disease. Abnormal nitric oxide–dependent regulation of vascular tone, adhesion, platelet activation, and inflammation contributes to the pathophysiology of vaso-occlusion. Nitric oxide may have promise as a mechanism-of-disease–based therapy for treatment of vaso-occlusion. Objective  To explore the efficacy and safety of inhaled nitric oxide (INO) for treatment of vaso-occlusive crisis in pediatric patients. Design  Prospective, double-blind, placebo-controlled, randomized clinical trial with enrollment between September 1999 and October 2001. Setting  Urban, tertiary care children's hospital in the United States. Participants  Twenty patients aged 10 to 21 years with sickle cell disease and severe acute vaso-occlusive crisis. Intervention  Patients were randomly assigned to receive INO (80 ppm with 21% final concentration of inspired oxygen; n = 10), or placebo (21% inspired oxygen; n = 10) for 4 hours. Main Outcome Measures  Change in pain at 4 hours of inhalation compared with preinhalation pain, measured on a 10-cm visual analog scale (VAS); secondary outcome measures were pain over 6 hours, parenteral narcotic use over 24 hours, duration of hospitalization, blood pressure, oxygen saturation, and methemoglobin concentration. Results  Preinhalation VAS pain scores were similar in the INO and placebo groups (P = .80). The decrease in VAS pain scores at 4 hours was 2.0 cm in the INO group and 1.2 cm in the placebo group (P = .37). Repeated-measures analysis of variance for hourly pain scores showed a 1-cm/h greater reduction in the INO group than the placebo group (P = .02). Morphine use over 6 hours was significantly less in the INO group (mean cumulative use, 0.29 vs 0.44 mg/kg; P = .03) but was not different over 4 hours (0.26 vs 0.32 mg/kg; P = .21) or 24 hours (0.63 vs 0.91 mg/kg; P = .15). Duration of hospitalization was 78 and 100 hours in the INO and placebo groups, respectively (P = .19). No INO toxicity was observed. Conclusions  Results of this exploratory study suggest that INO may be beneficial for acute vaso-occlusive crisis. These preliminary results warrant further investigation.      

Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial

Context  The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease (CAD) and normal blood pressure remains uncertain. Objective  To compare the effects of amlodipine or enalapril vs placebo on cardiovascular events in patients with CAD. Design, Setting, and Participants  Double-blind, randomized, multicenter, 24-month trial (enrollment April 1999-April 2002) comparing amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD (>20% stenosis by coronary angiography) and diastolic blood pressure <100 mm Hg. A substudy of 274 patients measured atherosclerosis progression by intravascular ultrasound (IVUS). Interventions  Patients were randomized to receive amlodipine, 10 mg; enalapril, 20 mg; or placebo. IVUS was performed at baseline and study completion. Main Outcome Measures  The primary efficacy parameter was incidence of cardiovascular events for amlodipine vs placebo. Other outcomes included comparisons of amlodipine vs enalapril and enalapril vs placebo. Events included cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina pectoris, hospitalization for congestive heart failure, fatal or nonfatal stroke or transient ischemic attack, and new diagnosis of peripheral vascular disease. The IVUS end point was change in percent atheroma volume. Results  Baseline blood pressure averaged 129/78 mm Hg for all patients; it increased by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4 mm Hg in the amlodipine and enalapril groups, respectively (P<.001 for both vs placebo). Cardiovascular events occurred in 151 (23.1%) placebo-treated patients, in 110 (16.6%) amlodipine-treated patients (hazard ratio [HR], 0.69; 95% CI, 0.54-0.88 [P = .003]), and in 136 (20.2%) enalapril-treated patients (HR, 0.85; 95% CI, 0.67-1.07 [P = .16]. Primary end point comparison for enalapril vs amlodipine was not significant (HR, 0.81; 95% CI, 0.63-1.04 [P = .10]). The IVUS substudy showed a trend toward less progression of atherosclerosis in the amlodipine group vs placebo (P = .12), with significantly less progression in the subgroup with systolic blood pressures greater than the mean (P = .02). Compared with baseline, IVUS showed progression in the placebo group (P<.001), a trend toward progression in the enalapril group (P = .08), and no progression in the amlodipine group (P = .31). For the amlodipine group, correlation between blood pressure reduction and progression was r = 0.19, P = .07. Conclusions  Administration of amlodipine to patients with CAD and normal blood pressure resulted in reduced adverse cardiovascular events. Directionally similar, but smaller and nonsignificant, treatment effects were observed with enalapril. For amlodipine, IVUS showed evidence of slowing of atherosclerosis progression.      

Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial

Context  Basic research provides plausible mechanisms and observational studies suggest that apparently healthy persons, who self-select for high intakes of vitamin E through diet or supplements, have decreased risks of cardiovascular disease and cancer. Randomized trials do not generally support benefits of vitamin E, but there are few trials of long duration among initially healthy persons. Objective  To test whether vitamin E supplementation decreases risks of cardiovascular disease and cancer among healthy women. Design, Setting, and Participants  In the Women’s Health Study conducted between 1992 and 2004, 39 876 apparently healthy US women aged at least 45 years were randomly assigned to receive vitamin E or placebo and aspirin or placebo, using a 2 x 2 factorial design, and were followed up for an average of 10.1 years. Intervention  Administration of 600 IU of natural-source vitamin E on alternate days. Main Outcome Measures  Primary outcomes were a composite end point of first major cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and total invasive cancer. Results  During follow-up, there were 482 major cardiovascular events in the vitamin E group and 517 in the placebo group, a nonsignificant 7% risk reduction (relative risk [RR], 0.93; 95% confidence interval [CI], 0.82-1.05; P = .26). There were no significant effects on the incidences of myocardial infarction (RR,  1.01; 95% CI, 0.82-1.23; P = .96) or stroke (RR, 0.98; 95% CI, 0.82-1.17; P = .82), as well as ischemic or hemorrhagic stroke. For cardiovascular death, there was a significant 24% reduction (RR, 0.76; 95% CI, 0.59-0.98; P = .03). There was no significant effect on the incidences of total cancer (1437 cases in the vitamin E group and 1428 in the placebo group; RR, 1.01; 95% CI, 0.94-1.08; P = .87) or breast (RR, 1.00; 95% CI, 0.90-1.12; P = .95), lung (RR, 1.09; 95% CI, 0.83-1.44; P = .52), or colon cancers (RR, 1.00; 95% CI, 0.77-1.31; P = .99). Cancer deaths also did not differ significantly between groups. There was no significant effect of vitamin E on total mortality (636 in the vitamin E group and 615 in the placebo group; RR, 1.04; 95% CI, 0.93-1.16; P = .53). Conclusions  The data from this large trial indicated that 600 IU of natural-source vitamin E taken every other day provided no overall benefit for major cardiovascular events or cancer, did not affect total mortality, and decreased cardiovascular mortality in healthy women. These data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention among healthy women.      

Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial

Context  Ziconotide (formerly SNX-111) selectively blocks N-type voltage-sensitive calcium channels and may be effective in patients with pain that is refractory to opioid therapy or those with intolerable opioid-related adverse effects. Objective  To assess the safety and efficacy of intrathecal ziconotide in patients with pain that is refractory to conventional treatment. Design, Setting, and Patients  Double-blind, placebo-controlled, randomized trial conducted from March 12, 1996, to July 11, 1998, at 32 study centers in the United States, Australia, and the Netherlands. Patients were 111 individuals ages 24 to 85 years with cancer or AIDS and a mean Visual Analog Scale of Pain Intensity (VASPI) score of 50 mm or greater. Patients were randomly assigned in a 2:1 ratio to receive ziconotide or placebo treatment. Interventions  Intrathecal ziconotide was titrated over 5 to 6 days, followed by a 5-day maintenance phase for responders and crossover of nonresponders to the opposite treatment group. Main Outcome Measure  Mean percentage change in VASPI score from baseline to the end of the initial titration period. Results  Of the evaluable population, 67 (98.5%) of 68 patients receiving ziconotide and 38 (95%) of 40 patients receiving placebo were taking opioids at baseline (median morphine equivalent dosage of 300 mg/d for the ziconotide group and 600 mg/d for the placebo group; P = .63, based on mean values), and 36 had used intrathecal morphine. Mean (SD) VASPI scores were 73.6 (1.8) mm in the ziconotide group and 77.9 (2.3) mm in the placebo group (P = .18). Mean VASPI scores improved 53.1% (95% confidence interval [CI], 44.0%-62.2%) in the ziconotide group and 18.1% (95% CI, 4.8%-31.4%) in the placebo group (P<.001), with no loss of efficacy of ziconotide in the maintenance phase. Pain relief was moderate to complete in 52.9% of patients in the ziconotide group compared with 17.5% in the placebo group (P<.001). Five patients receiving ziconotide achieved complete pain relief, and 50.0% of patients receiving ziconotide responded to therapy compared with 17.5% of those receiving placebo (P = .001). Conclusion  Intrathecal ziconotide provided clinically and statistically significant analgesia in patients with pain from cancer or AIDS.