Alice White

Association of Hormone-Replacement Therapy with Various Cardiovascular Risk Factors in Postmenopausal Women

Background Most epidemiologic studies of cardiovascular disease in postmenopausal women suggest that estrogen-replacement therapy has a protective effect. The effects of the use of estrogen combined with progestin are less well studied. Methods To examine the associations of hormone-replacement therapy with concentrations of plasma lipids and hemostatic factors, fasting serum concentrations of glucose and insulin, and blood pressure, we studied 4958 postmenopausal women participating in a population-based investigation. Using cross-sectional data, we classified the women into four groups according to their use of hormone-replacement therapy: current users of estrogen alone, current users of estrogen with progestin, nonusers who had formerly used these hormones, and nonusers who had never used them. Results Current users had higher mean levels of high-density lipoprotein cholesterol, its subfractions high-density lipoprotein2 and high-density lipoprotein3, and apolipoprotein A-I than nonusers, and lower me...

The causal role for genital ulcer disease as a risk factor for transmission of human immunodeficiency virus : An application of the Bradford Hill criteria

Background and Objectives: Genital ulcer disease (GUD) has been reported to increase the risk for the acquisition of human immunodeficiency virus (HIV). Although many investigators have reported an increased risk for HIV infection in persons with concurrent or previous GUD, not all studies have been designed to determine whether GUD causes an increased risk for HIV infection or acts only as a risk marker for infection. The evidence from the literature is discussed, and the criteria for causal inference proposed by Sir Austin Bradford Hill are applied. Goal: To evaluate the strength of the association between GUD and infection by HIV. Study Design: Case‐control, cross‐sectional, and cohort studies that examined the association between HIV seroconversion and GUD were chosen from the literature. Twenty‐seven epidemiologic studies were selected for analysis, many of which reported separate analyses of the association between HIV infection and herpes simplex virus infection, syphilis, or nonspecified GUD. The studies were analyzed to investigate the magnitude of association between GUD and HIV, and the evidence evaluated using Hills criteria. Results: Approximately two thirds of the analyses reported a statistically significant association between GUD and HIV infection. Fourteen studies reported 29 separate analyses using a case‐control design, 18 of which reported a statistically significant association between GUD (GUD, herpes, and syphilis) and HIV infection, four analyses were of varying significance depending on the analytical technique used, and seven were nonsignificant. Thirteen studies reported 23 separate longitudinal analyses that used a nested case‐control or cohort design: 11 reported a significant association, 11 had nonsignificant findings, and results of one study varied. No study reported a statistically significant negative association. When applying the literature to Hills criteria, all nine criteria for causal inference were met, providing additional evidence that genital ulcers are associated with an increased risk for the development of HIV infection. Conclusions: The published evidence suggests that GUD increases the risk for HIV acquisition. Few studies, however, have examined carefully the temporal association between preexisting GUD and subsequent HIV acquisition. The analyses that simultaneously controlled for additional risks for HIV infection, such as lifetime sex partners or history of injection drug use, report a generally lower risk for HIV associated with GUD. It is likely that studies that adequately control for risk factors will find a lower risk associated with GUD than was reported in the literature earlier in the HIV epidemic. Future research needs and the problems associated with conducting these types of studies are discussed.

Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: A pharmaceutical company commitment

OBJECTIVE Glaxo Wellcome becomes aware of prenatal exposures to its medications as early as the clinical trial phase of development. An international process for monitoring prenatal exposure to all Glaxo Wellcome medicines has been developed. For specific products there are prospective pregnancy registries. STUDY DESIGN The registries are observational, case-registration, and follow-up studies designed to detect evidence of teratogenicity associated with specific medications. After prenatal exposure to the registry medication, pregnancies are registered prospectively, through voluntary reports by health care providers. An advisory committee of independent scientists for each registry reviews data and advises in dissemination of information. Risk of birth defects, as defined by the Centers for Disease Control and Prevention, is compared with published risks both in women in the general population and in women with the underlying condition being treated, if available. RESULTS The following data show results from the prospective first-trimester exposures registered since establishment of each registry. The published risk of birth defects in the general population range is 3% to 5%, and the risk in women with epilepsy is 6% to 9%. The proportions of outcomes with birth defects are as follows: in the Acyclovir (antiviral medication) Pregnancy Registry (1984-1998) (19/581), 3.3% (95% confidence interval, 2.0%-5.2%); in the Lamotrigine (monotherapy and polytherapy antiepileptic medication) Pregnancy Registry (1992-September 1998) (8/123), 6.5% (95% confidence interval, 3.1%-12.8%); in the Sumatriptan (migraine medication) Pregnancy Registry (1996-October 1998) (7/183), 3.8% (95% confidence interval, 1.7%-8.0%). The Valacyclovir, Bupropion, and Naratriptan registries have insufficient data for analysis. CONCLUSION None of the registries has provided a risk estimate exceeding that expected in the disorder treated, and no pattern of defects has been observed. Whereas information from the larger registries is reassuring regarding risk, these studies cannot rule out possible small excess risks from use of these drugs in pregnancy. Data obtained through these registries are shared with the medical community as a supplement to animal toxicology studies to assist in weighing potential risks and benefits of treatment for individual patients. The success of the registries depends on the continued willingness of the obstetrics and gynecology community to notify the registries of prenatal exposures.

Experience of healthcare workers taking postexposure prophylaxis after occupational HIV exposures: findings of the HIV Postexposure Prophylaxis Registry.

OBJECTIVE To collect information about the safety of taking antiretroviral drugs for human immunodeficiency virus (HIV) postexposure prophylaxis (PEP). DESIGN A voluntary, confidential registry. SETTING Hospital occupational health clinics, emergency departments, private physician offices, and health departments in the United States. RESULTS 492 healthcare workers (HCWs) who had occupational exposures to HIV, were prescribed HIV PEP, and agreed to be enrolled in the registry by their healthcare providers were prospectively enrolled in the registry. Three hundred eight (63%) of 492 of the PEP regimens prescribed for these HCWs consisted of at least three antiretroviral agents. Of the 449 HCWs for whom 6-week follow-up was available, 195 (43%) completed the PEP regimen as initially prescribed. Forty-four percent (n=197) of HCWs discontinued all PEP drugs and did not complete a PEP regimen. Thirteen percent (n=57) discontinued > or =1 drug or modified drug dosage or added a drug but did complete a course of PEP Among the 254 HCWs who modified or discontinued the PEP regimen, the two most common reasons for doing so were because of adverse effects attributed to PEP (54%) and because the source-patient turned out to be HIV-negative (38%). Overall, 340 (76%) HCWs with 6-week follow-up reported some symptoms while on PEP: nausea (57%), fatigue or malaise (38%), headache (18%), vomiting (16%), diarrhea (14%), and myalgias or arthralgias (6%). The median time from start of PEP to onset of each of the five most frequently reported symptoms was 3 to 4 days. Only 37 (8%) HCWs with 6-week follow-up were reported to have laboratory abnormalities; review of the reported abnormalities revealed that most were unremarkable. Serious adverse events were reported to the registry for 6 HCWs; all but one event resolved by the 6-month follow-up visit. Fewer side effects were reported by HCWs taking two-drug PEP regimens than by HCWs taking three-drug PEP regimens. CONCLUSIONS Side effects from HIV PEP were very common but were rarely severe or serious. The nature and frequency of HIV PEP toxicity were consistent with information already available on the use of these antiretroviral agents. Clinicians prescribing HIV PEP need to counsel HCWs about PEP side effects and should know how to manage PEP toxicity when it arises.

Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters

BACKGROUND To estimate the clinical benefit of highly active antiretroviral therapy (HAART) initiation vs deferral in a given month in patients with CD4 cell counts less than 800/μL. METHODS In this observational cohort study of human immunodeficiency virus type 1 seroconverters from CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe), we constructed monthly sequential nested subcohorts between January 1996 and May 2009, including all eligible HAART-naive, AIDS-free individuals with a CD4 cell count less than 800/μL. The primary outcome was time to AIDS or death in those who initiated HAART in the baseline month compared with those who did not, pooled across subcohorts and stratified by CD4 cell count. Using inverse probability-of-treatment weighted survival curves and Cox proportional hazards regression models, we estimated the absolute and relative effects of treatment with robust 95% confidence intervals (CIs). RESULTS Of 9455 patients with 52,268 person-years of follow-up, 812 (8.6%) developed AIDS and 544 (5.8%) died. In CD4 cell count strata of 200 to 349, 350 to 499, and 500 to 799/μL, HAART initiation was associated with adjusted hazard ratios (95% CIs) for AIDS/death of 0.59 (0.43-0.81), 0.75 (0.49-1.14), and 1.10 (0.67-1.79), respectively. In the analysis of all-cause mortality, HAART initiation was associated with adjusted hazard ratios (95% CIs) of 0.71 (0.44-1.15), 0.51 (0.33-0.80), and 1.02 (0.49-2.12), respectively. Numbers needed to treat (95% CIs) to prevent 1 AIDS event or death within 3 years were 21 (14-38) and 34 (20-115) in CD4 cell count strata of 200 to 349 and 350 to 499/μL, respectively. CONCLUSION Compared with deferring in a given month, HAART initiation at CD4 cell counts less than 500/μL (but not 500-799/μL) was associated with slower disease progression.

No Association of Menopause and Hormone Replacement Therapy With Carotid Artery Intima-Media Thickness

BACKGROUND Cardiovascular disease is the major cause of death in older women. Information on the relation of menopause and hormone replacement therapy with carotid atherosclerosis is limited. METHODS AND RESULTS We examined cross-sectionally the association of menopausal status, years since last menstruation, and hormone replacement therapy status with carotid artery intima-media thickness as determined by B-mode ultrasound. Female participants (n = 5436) in the Atherosclerosis Risk in Communities Study without a history of symptomatic cardiovascular disease were included in the analyses. Menopause status in 45- to 54-year-old women who had never used hormone replacement therapy was not strongly associated with carotid intima-media thickness (mean = 0.65 mm and 0.67 mm in premenopausal and postmenopausal women, respectively, adjusted for age, race, cigarette years of smoking, body mass index, sport index, systolic blood pressure, use of blood pressure medications, drinking status, diabetes, and education level). In postmenopausal women aged 55 to 64 years, women with < or = 5 years since last menstruation had an adjusted average intima-media thickness (0.74 mm) comparable to those with > 5 years since last menstruation (0.75 mm) (P > .05). Although hormone replacement therapy use was associated with a more favorable lipid and hemostasis profile than nonuse, its use was not associated with intima-media thickness in postmenopausal women aged 55 to 64 years (adjusted average = 0.74 mm for current users of estrogen alone and approximately 0.75 mm each for current users of estrogen plus progestin, former users, and never users). CONCLUSIONS The data suggest that the well-known associations of hormone replacement therapy with reductions in atherosclerotic cardiovascular disease may be attributable more to acute physiological effects, such as hemodynamic changes or reduced thrombosis, than to atherosclerosis itself.

Sex and race differences in short-term prognosis after acute coronary heart disease events: The Atherosclerosis Risk In Communities (ARIC) study

BACKGROUND Case fatality after myocardial infarction (MI) among patients admitted to the hospital may differ between men and women and blacks and whites. Furthermore, a different pattern of sex and race differences in case fatality may occur when coronary deaths outside the hospital are included in the analysis. The ARIC study provides community-based data to examine 28-day case fatality rates after coronary heart disease (CHD) events. METHOD AND RESULTS Surveillance of out-of-hospital CHD deaths and hospitalized MI was conducted in 4 U.S. communities from 1987 to 1993. Hospital discharges and death certificates were sampled, medical records abstracted, and interviews conducted with witnesses of out-of-hospital deaths. MI and out-of-hospital death classifications followed a standard algorithm. Linkage of hospitalized MIs to fatality within 28 days ensured complete ascertainment of case fatality rate. Comorbidities and complications during hospital stay were compared to assess possible explanatory factors for differences in case fatality. Overall, age-adjusted 28-day case fatality (MI plus CHD) was higher in black men compared with white men (odds ratio 1.78, 95% confidence interval 1.4-2.2) and in black women compared with white women (odds ratio 1.5, 95% confidence interval 1. 2-2.0). Although men had higher overall case fatality rates than did women, this difference was not statistically significant. After a hospitalized MI, 28-day case fatality rate was not statistically significantly different between men compared with women or blacks compared with whites. CONCLUSION Race and sex differences in case fatality after hospitalized MI were not evident in these data, although when out-of-hospital deaths were included, men and blacks were more likely than women and whites to die within 28 days of an acute cardiac event. A majority of deaths occurred before hospital admission, and additional study of possible reasons for these differences should be a priority.

Antenatal steroids and neonatal outcomes in controlled clinical trials of surfactant replacement

A substantial body of scientific data stretching over more than 20 years indicates that prenatal steroids are safe and effective in improving pregnancy outcome among women in premature labor.‘-* A meta-analysis published in 1990 of more than 3000 infants in 12 different randomized clinical trials of antenatal steroids conducted before surfactant showed conclusively that prenatal steroids significantly reduced necrotizing enterocolitis (NEC), intraventricular hemorrhage (MI), and neonatal mortality.’ Nevertheless, prenatal steroids were and still are far from universally used among women at risk of preterm labor, particularly in the United States. The purpose of this article is to describe the results of retrospective analyses of the association of prenatal steroids with perinatal morbidity and mortality among infants enrolled in randomized clinical trials of surfactant replacement therapy.

Serum cholesterol and 20-year mortality in black and white men and women aged 65 and older in the evans county heart study

Serum cholesterol and 20-year mortality rates were studied in 396 Evans County black and white men and women who were 65 years and older and free of prevalent coronary heart disease (CHD) at baseline examination in 1960 to 1962. Previous reports on Evans County men and women younger than 65 found cholesterol levels to be significantly associated with all-cause and CHD mortality in white men, with CHD mortality in black men, and with cardiovascular disease mortality in white women. The independent role of total serum cholesterol as a predictor of CHD and all-cause mortality in the 65-and-older age group was evaluated using Cox proportional hazards models. Among white men, serum cholesterol level was positively associated with CHD mortality (relative risk of 1.54, P < 0.05 for an increment of 40 mg/dL [1.03 mmol/L], or one standard deviation in cholesterol). A significant J-shaped relationship of cholesterol with all-cause mortality was found among white men. Among black women, cholesterol was negatively associated with all-cause mortality. Neither all-cause nor CHD mortality was related to serum cholesterol among black men or white women. Although based on small numbers, the results of this study suggest that in Evans County, total serum cholesterol is an independent predictor of mortality in white men aged 65 and over, while these results should not be generalized to other race-gender groups in this cohort.

Comparison of symptoms of influenza A with abacavir-associated hypersensitivity reaction

Differentiation between abacavir hypersensitivity and viral respiratory infections is problematic. Fifteen cases of abacavir hypersensitivity were matched to 30 controls with culture proven influenza A with no abacavir exposure. Rash was associated with hypersensitivity (odds ratio [OR] = 13.1, P = 0.02) as was the presence of nausea (OR = 30, P < 0.001), vomiting (OR = 17.1, P = 0.001) or diarrhoea (OR = 22, P < 0.001). The number of gastrointestinal symptoms was also predictive of hypersensitivity reaction (P < 0.001). Respiratory symptoms (cough, sore throat, or dyspnoea) were not associated with abacavir hypersensitivity (OR = 0.08, P = 0.001). Multivariate analysis confirmed the following associations for abacavir hypersensitivity: the number of gastrointestinal symptoms (OR = 8.6, P = 0.0032), cough (OR = 0.039, P = 0.02) and rash (OR = 16.9, P = 0.07). Abacavir hypersensitivity is strongly associated with gastrointestinal (GI) symptoms. Cough without GI symptoms is associated with influenza.