Steven Grinspoon

Metabolic Abnormalities and Cardiovascular Disease Risk Factors in Adults with Human Immunodeficiency Virus Infection and Lipodystrophy

We evaluated metabolic and clinical features of 71 HIV-infected patients with lipodystrophy by comparing them with 213 healthy control subjects, matched for age and body mass index, from the Framingham Offspring Study. Thirty HIV-infected patients without fat redistribution were compared separately with 90 matched control subjects from the Framingham Offspring Study. Fasting glucose, insulin, and lipid levels; glucose and insulin response to standard oral glucose challenge; and anthropometric measurements were determined. HIV-infected patients with lipodystrophy demonstrated significantly increased waist-to-hip ratios, fasting insulin levels, and diastolic blood pressure compared with controls. Patients with lipodystrophy were more likely to have impaired glucose tolerance, diabetes, hypertriglyceridemia, and reduced levels of high-density lipoprotein (HDL) cholesterol than were controls. With the exception of HDL cholesterol level, these risk factors for cardiovascular disease (CVD) were markedly attenuated in patients without lipodystrophy and were not significantly different in comparison with controls. These data demonstrate a metabolic syndrome characterized by profound insulin resistance and hyperlipidemia. CVD risk factors are markedly elevated in HIV-infected patients with fat redistribution.

Fracture Prevalence among Human Immunodeficiency Virus (HIV)-Infected Versus Non-HIV-Infected Patients in a Large U.S. Healthcare System

CONTEXT Reduced bone mineral density has been demonstrated among HIV-infected patients, but fracture prevalence is unknown. OBJECTIVE The objective of the study was to compare fracture prevalence in HIV-infected and non-HIV-infected patients. DESIGN This was a population-based study. SETTING The study was conducted at a large U.S. health care system. PATIENTS A total of 8525 HIV-infected and 2,208,792 non-HIV-infected patients with at least one inpatient or outpatient encounter between October 1, 1996, and March 21, 2008, was compared. MAIN OUTCOME MEASURE Fracture prevalence using specific International Classification of Diseases, Ninth Revision, Clinical Modification fracture codes was measured. RESULTS The overall fracture prevalence was 2.87 vs. 1.77 patients with fractures per 100 persons in HIV-infected, compared with non-HIV-infected patients (P < 0.0001). Among females, the overall fracture prevalence was 2.49 vs. 1.72 per 100 persons in HIV-infected vs. non-HIV-infected patients (P = 0.002). HIV-infected females had a higher prevalence of vertebral (0.81 vs. 0.45; P = 0.01) and wrist (1.31 vs. 0.83; P = 0.01) fractures per 100 persons, compared with non-HIV-infected females but had a similar prevalence of hip fractures (0.47 vs. 0.56; P = 0.53). Among males, the fracture prevalence per 100 persons was higher in HIV-infected vs. non-HIV-infected patients for any fracture (3.08 vs. 1.83; P < 0.0001), vertebral fractures (1.03 vs. 0.49; P < 0.0001), hip fractures (0.79 vs. 0.45; P = 0.001), and wrist fractures (1.46 vs. 0.99; P = 0.001). Fracture prevalence was higher relative to non-HIV-infected patients among African-American and Caucasian females and Caucasian males. CONCLUSIONS Fracture prevalence is increased in HIV-infected compared with non-HIV-infected patients.

Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel.

Objective: Alterations in glucose and lipid metabolism, lactic acidemia, bone disorders, and abnormal body fat distribution have been recognized recently as frequent complications associated with HIV‐1 infection and potent antiretroviral therapy, but limited data ate available regarding the appropriate management of these disorders. These recommendations were developed to guide physicians actively involved in HIV care in the management of metabolic complications that occur primarily within the context of potent antiretroviral therapy. Participants: A 12‐member panel representing international expertise in HIV‐1 patient care, antiretroviral therapy, and endocrine and metabolic disorders was selected in the spring of 2000 by the International AIDS Society‐USA, a not‐for‐profit physician education organization. Panel members met in closed meetings beginning in May 2000. All work was funded by the International AIDS Society‐USA; the panel members are not compensated for their participation. Evidence: The panel reviewed published results of clinical, epidemiologic, and basic science studies and data and abstracts presented at research conferences, primarily from 1997 to 2002. The panel also considered studies of the pathophysiology and treatment of similar metabolic abnormalities in noninfected persons. Emphasis was placed on results from prospective, randomized, controlled clinical trials when available. Process: For each metabolic complication, 1 or more member(s) reviewed and presented all available evidence to the panel, and then wrote a summary of the evidence and preliminary recommendations. Final recommendations were determined by full group consensus. The summaries were combined into a single working document and all panel members edited and approved all subsequent drafts. Conclusions: Carefully controlled studies to determine the incidence, etiology, risk factors, and most appropriate treatments for metabolic complications in HIV‐1 infection are urgently needed. In the absence of these data, and to prevent acute illness and mitigate long‐term risks, the panel recommends routine assessment and monitoring of glucose and lipid levels and assessment and monitoring of lactic acidemia and bone abnormalities if clinical signs or symptoms are detected. With the exception of body fat distribution abnormalities, specific treatments for these complications are also recommended. Successful long‐term antiretroviral therapy will require diligent monitoring and preemptive treatment of metabolic complications to optimize the riskbenefit ratio of antiretroviral therapies.

Prevalence and predictive factors for regional osteopenia in women with anorexia nervosa.

Anorexia nervosa is highly prevalent among U.S. women (1, 2) and is associated with substantial bone loss (3-6). Bone loss in women with this disorder is multifactorial; is related in part to estrogen deficiency and to direct effects of undernutrition (3, 4, 7); and is rapid, often occurring within 6 months of disease onset (4) and persisting to some degree after weight recovery (8). It is important to determine the prevalence of regional bone loss at different skeletal sites because it may predict site-specific fracture rates (9). We therefore measured bone mineral density (BMD) at several skeletal sites to determine the prevalence rates and predictive factors of regional osteopenia and osteoporosis in a large community-based sample of women with anorexia nervosa. Methods We studied 130 women with anorexia nervosa recruited through community advertisements and community physician referral. Telephone screening interviews were used to exclude patients who reported normal weight and menses; use of bisphosphonates, calcitonin, or glucocorticoids; or medical conditions other than anorexia nervosa that are known to affect BMD. Women who had regular uterine withdrawal bleeding while receiving estrogen therapy and women with concomitant bulimia nervosa were permitted to participate. Eligible patients underwent a 3-hour outpatient visit at the General Clinical Research Center of the Massachusetts General Hospital in Boston. Height, weight, age at menarche, time since last menstrual period, previous and current estrogen use, fracture history, and frame size were determined. Calcium and vitamin D intake were determined by diet history in a subset of 60 patients. The diagnosis of anorexia nervosa, according to criteria specified in Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was confirmed in all patients (10). All patients gave written consent, as required by the Subcommittee on Human Studies. Bone mineral density at the anteriorposterior lumbar spine (L1L4), lateral spine, left total hip, femoral neck, and greater trochanter was determined with dual-energy x-ray absorptiometry using a Hologic 4500 densitometer (Hologic, Inc., Waltham, Massachusetts) (lumbar spine SD, 0.01 g/cm2) (11). At each skeletal site, patients were categorized as having normal BMD (T-score>1.0 SD), osteopenia (1.0 SD T-score>2.5 SD), or osteoporosis (T-score 2.5 SD), according to World Health Organization criteria. Data on BMD in a subset of 30 patients were published previously (7). Wrist and frame size were determined (12, 13), and body mass index and percentage of ideal body weight were calculated (14). Age at menarche and time since last menstrual period were assessed for all patients. Whenever possible, total duration of amenorrhea since menarche was determined (n =78). Current and previous lifetime estrogen use, including type of estrogen, was quantified and categorized for each patient. We used the MantelHaenszel test to compare BMD at the anteriorposterior and lateral spine, stratifying on patients. Standard least-squares multivariate regression models were constructed for each skeletal site by using age, age at menarche, time since last menstrual period, weight, height, wrist size, and fracture history as covariates. Covariates were chosen in advance as important clinical variables affecting BMD. Adjusted regression coefficients and confidence intervals were determined for each covariate. Data are expressed as the mean SE. The funding source had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Clinical data and data on BMD are shown in Table 1. Ninety-eight percent of patients were white and 2% were Asian. Mean T-scores were 1.4 0.1 SD for the anteriorposterior spine, 1.8 0.1 SD for the lateral spine, and 1.4 0.1 SD for the total hip. Twenty-six percent of patients (n =34) reported a history of fracture (foot or ankle [n =6], hand or wrist [n =7], leg [n =1], arm or elbow [n =4], stress fracture [n =5], and other fracture [n =11]). Table 1. Clinical Characteristics of Study Patients and Comparison by Estrogen Use and Menstrual History Osteopenia and osteoporosis, respectively, were seen at the anteriorposterior spine in 50% and 13% of patients, at the lateral spine in 57% and 24% of patients, and at the total hip in 47% and 16% of patients. Normal BMD was seen at the anteriorposterior spine in only 37% of patients, at the lateral spine in 19% of patients, and at the total hip in 37% of patients. Results of lateral and anteriorposterior spinal tests of BMD were discordant in 36 patients, of whom 31 had normal BMD at the anteriorposterior spine (T-score>1.0) but low BMD at the lateral spine (T-score 1.0) (P<0.001). Bone mineral density was reduced by at least 1.0 SD at one or more skeletal sites in 92% of patients and by at least 2.5 SD in 38% of patients. No differences in BMD were observed between patients with anorexia nervosa alone and patients with anorexia nervosa and concomitant bulimia nervosa (P>0.05 at all sites; data not shown). Twenty-three percent of patients were current estrogen users (mean duration, 25.3 5.4 months) and 58% were previous estrogen users (mean duration, 23.9 3.1 months). Bone mineral density did not differ at any site according to current or previous estrogen use (Table 1). Age, body mass index, and age at menarche were similar in the subgroup comparisons according to estrogen status. Oral contraceptives were used in all but 3 of the current estrogen users (10%) and all but 7 of the ever-estrogen users (10%); these 10 women received conjugated estrogen. Similar results were obtained in a subanalysis limited to the patients receiving oral contraceptives (data not shown). Total duration of estrogen use was not correlated with BMD at the anteriorposterior spine, lateral spine, femoral neck, total hip, trochanter, or total body (P>0.10 for all comparisons). Patients with primary amenorrhea (n =7) weighed less and had lower BMD at all sites than patients with secondary amenorrhea (n =123) (Table 1), although sample size was small in the primary amenorrhea group. Total calcium intake was not correlated with BMD at any site (P>0.1 for all sites). Fifty-seven percent of patients were receiving calcium supplements, 53% were receiving a multivitamin containing 400 IU of vitamin D, and 43% were receiving both. Bone mineral density did not differ in patients receiving nutritional supplements (data not shown). Weight was a significant independent predictor of BMD at all skeletal sites (Table 2). Patients with normal BMD, osteopenia, and osteoporosis at the total hip weighed 48.7 0.8 kg, 45.9 0.8 kg, and 39.0 0.7 kg, respectively. Similar trends were seen at other skeletal sites (data not shown). Age at menarche was a significant independent predictor of BMD measured by anteriorposterior spinal densitometry. Time since last menstrual period was a significant predictor of BMD at the anteriorposterior and lateral spine. Our results were similar when we used multivariate regression models with total duration of amenorrhea instead of last menstrual period in patients for whom this information was available (n =78) (data not shown). Table 2. Univariate and Multivariate Regression Analyses Discussion Our data demonstrate the high prevalence and profound degree of site-specific bone loss in women with anorexia nervosa. Our study design had advantages: Patients were recruited from the community and were not preselected for bone loss, and we evaluated bone loss at several skeletal sites. Although weight was highly significant as a predictor of bone loss at all sites, time since last menstrual period and age at menarche were significant predictive factors for BMD at the anteriorposterior spine, suggesting a greater relative influence of estrogen deficiency at this site. Other mechanisms may also contribute to reduced BMD in patients with anorexia nervosa, such as failure to achieve peak BMD, hypercortisolemia, and reduced vitamin D intake (4). However, we did not see any association between calcium or vitamin D intake and BMD. Increased risk for fracture is the major clinical implication of bone loss in women with anorexia nervosa. Fracture risk doubles with each decrease of 1 SD in BMD (9). Our data therefore suggest that patients with anorexia are at a markedly increased risk for fracture at many skeletal sites. A relatively high percentage of patients reported a previous history of fracture, but because radiologic confirmation was not obtained, relative risk for fracture was not determined. Bone mineral density was reduced by at least 1.0 SD at one or more skeletal sites in 97% of women with fractures, but fracture site was not correlated with the location of osteopenia. Although our study was not designed to prospectively investigate the efficacy of estrogen use in women with anorexia nervosa, no effect of previous or current estrogen use on BMD was demonstrated at any skeletal sites. These retrospective data stand in partial contrast to cross-sectional data from a previous study, which suggested an effect of estrogen exposure at the lumbar spine but not at other sites (15). The minimal effect of estrogen exposure on BMD in our study is consistent with that seen in a previous randomized study, which showed no effect of estrogenprogestin replacement therapy on BMD in patients with anorexia nervosa (16). The effectiveness of estrogen in increasing or preserving BMD in women with anorexia nervosa may be mitigated by continued undernutrition, which may act to uncouple bone formation and resorption. We have previously shown that women with anorexia nervosa exhibit low bone formation rates and increased resorption rates (3). Hotta and colleagues (17) have shown that low rates of bone formation in patients with anorexia nervosa increase with feeding, suggesting a mechanism whereby bone formation is reduced by undernutrition and

Soluble CD163, a Novel Marker of Activated Macrophages, Is Elevated and Associated With Noncalcified Coronary Plaque in HIV-Infected Patients

BACKGROUND Pro-inflammatory monocytes/macrophages may contribute to increased atherosclerosis in human immunodeficiency virus (HIV)-infected patients. We investigate--to our knowledge, for the first time--sCD163 and other markers of monocyte activation in relationship to atherosclerotic plaque in HIV-infected patients. METHODS One hundred two HIV-infected and 41 HIV-seronegative men with equivalent cardiovascular risk factors and without history of coronary artery disease were prospectively recruited and underwent computed tomography coronary angiography. RESULTS sCD163 levels and presence of plaque were significantly higher among antiretroviral-treated subjects with undetectable HIV RNA levels, compared with seronegative controls (1172 ± 646 vs. 883 ± 561 ng/mL [P = .02] for sCD163 and 61% vs. 39% [P = .03] for presence of plaque). After adjusting for age, race, lipids, blood pressure, glucose, smoking, sCD14, and HIV infection, sCD163 remained independently associated with noncalcified plaque (P = .008). Among HIV-infected patients, sCD163 was associated with coronary segments with noncalcified plaque (r = 0.21; P = .04), but not with calcium score. In contrast, markers of generalized inflammation, including C-reactive protein level, and D-dimer were not associated with sCD163 or plaque among HIV-infected patients. CONCLUSIONS sCD163, a monocyte/macrophage activation marker, is increased in association with noncalcified coronary plaque in men with chronic HIV infection and low or undetectable viremia. These data suggest a potentially important role of chronic monocyte/macrophage activation in the development of noncalcified vulnerable plaque. CLINICAL TRIAL REGISTRATION NCT00455793.

Arterial inflammation in patients with HIV

CONTEXT Cardiovascular disease is increased in patients with human immunodeficiency virus (HIV), but the specific mechanisms are unknown. OBJECTIVE To assess arterial wall inflammation in HIV, using 18fluorine-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET), in relationship to traditional and nontraditional risk markers, including soluble CD163 (sCD163), a marker of monocyte and macrophage activation. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study of 81 participants investigated between November 2009 and July 2011 at the Massachusetts General Hospital. Twenty-seven participants with HIV without known cardiac disease underwent cardiac 18F-FDG-PET for assessment of arterial wall inflammation and coronary computed tomography scanning for coronary artery calcium. The HIV group was compared with 2 separate non-HIV control groups. One control group (n = 27) was matched to the HIV group for age, sex, and Framingham risk score (FRS) and had no known atherosclerotic disease (non-HIV FRS-matched controls). The second control group (n = 27) was matched on sex and selected based on the presence of known atherosclerotic disease (non-HIV atherosclerotic controls). MAIN OUTCOME MEASURE Arterial inflammation was prospectively determined as the ratio of FDG uptake in the arterial wall of the ascending aorta to venous background as the target-to-background ratio (TBR). RESULTS Participants with HIV demonstrated well-controlled HIV disease (mean [SD] CD4 cell count, 641 [288] cells/μL; median [interquartile range] HIV-RNA level, <48 [<48 to <48] copies/mL). All were receiving antiretroviral therapy (mean [SD] duration, 12.3 [4.3] years). The mean FRS was low in both HIV and non-HIV FRS-matched control participants (6.4; 95% CI, 4.8-8.0 vs 6.6; 95% CI, 4.9-8.2; P = .87). Arterial inflammation in the aorta (aortic TBR) was higher in the HIV group vs the non-HIV FRS-matched control group (2.23; 95% CI, 2.07-2.40 vs 1.89; 95% CI, 1.80-1.97; P < .001), but was similar compared with the non-HIV atherosclerotic control group (2.23; 95% CI, 2.07-2.40 vs 2.13; 95% CI, 2.03-2.23; P = .29). Aortic TBR remained significantly higher in the HIV group vs the non-HIV FRS-matched control group after adjusting for traditional cardiovascular risk factors (P = .002) and in stratified analyses among participants with undetectable viral load, zero calcium, FRS of less than 10, a low-density lipoprotein cholesterol level of less than 100 mg/dL (<2.59 mmol/L), no statin use, and no smoking (all P ≤ .01). Aortic TBR was associated with sCD163 level (P = .04) but not with C-reactive protein (P = .65) or D-dimer (P = .08) among patients with HIV. CONCLUSION Participants infected with HIV vs noninfected control participants with similar cardiac risk factors had signs of increased arterial inflammation, which was associated with a circulating marker of monocyte and macrophage activation.

Abnormal Bone Mineral Accrual in Adolescent Girls with Anorexia Nervosa

Anorexia nervosa (AN) is increasingly common in adolescent girls and occurs at a time of peak bone mass formation. Osteopenia is common in adolescent girls with AN, and in a cross-sectional study, we have reported low bone formation markers in such girls. To determine the impact of chronic undernutrition on bone mineral accrual in contrast to healthy controls, we prospectively measured bone mineral density (BMD) and body composition by dual energy x-ray absorptiometry, bone metabolism markers, and nutritional and hormonal status at baseline, 6 months, and 12 months in 19 adolescent girls with AN (mean +/- SEM, 15.4 +/- 0.4 yr) and 19 controls of comparable chronological and skeletal age. Overall, nutritional status in subjects with AN improved (mean percentage increase in body mass index from baseline, 9.2 +/- 1.9% and 15.2 +/- 2.6% at 6 and 12 months, respectively), with 11 subjects having recovered weight at 12 months. However, lumbar BMD at 12 months (AN, 0.88 +/- 0.02 g/cm(2), vs. control, 0.98 +/- 0.03 g/cm(2); P = 0.008) remained significantly reduced in AN compared with controls, even in recovered subjects. This was due to significant increases in lumbar BMD in controls vs. no change in AN subjects over the year (0.003 +/- 0.001 g/cm(2).month vs. 0.000 +/- 0.001 g/cm(2).month, respectively; P = 0.04). The most significant determinant of change in lumbar BMD at 12 months was change in lean body mass in both AN (r = 0.62; P = 0.008) and control (r = 0.80; P = 0.0006) groups. There were significant increases in surrogate markers of bone turnover in subjects with AN compared with controls as assessed by osteocalcin (AN, 0.9 +/- 0.4 micro g/liter.month, vs. control, -1.1 +/- 0.4 micro g/liter.month; P = 0.0007), bone-specific alkaline phosphatase (AN, 0.6 +/- 0.5 U/liter.month, vs. control, -1.5 +/- 0.4 U/liter.month; P = 0.002), deoxypyridinoline [AN, 0.1 +/- 0.1 nmol/mmol creatinine (cr).month, vs. control, -0.4 +/- 0.1 nmol/mmol cr.month; P = 0.005], and N-telopeptide (AN, 4 +/- 4 nmol BCE/mmol cr/month, vs. control, -9 +/- 4 nmol BCE/mmol cr/month; P = 0.01). Changes in IGF-I levels over the year were highly correlated with changes in bone turnover over the same period in AN (osteocalcin, r = 0.77; P = 0.001; deoxypyridinoline, r = 0.66; P = 0.01). A rise in N-telopeptide over the year was correlated with an increase in all bone mineral measures, including lumbar bone mineral content (r = 0.58; P = 0.03) and BMD (r = 0.53; P = 0.05) and total bone mineral content (r = 0.69; P = 0.006) and BMD (r = 0.69; P = 0.006) in the AN group. Therefore, despite recovery over 1 yr, poor bone mineral accrual persists in adolescent girls with AN in contrast to rapid bone accrual in healthy girls. Normalization of bone turnover markers occurs in association with nutritional recovery and an increase in the nutritionally dependent bone trophic factor IGF-I. A rise in bone turnover markers may be an early indicator of increase in BMD in recovering girls with AN.

Association of C-Reactive Protein and HIV Infection With Acute Myocardial Infarction

Objective:To investigate whether elevated C-reactive protein (CRP) levels and HIV infection are independently associated with acute myocardial infarction (AMI) among patients receiving care in a large US health care system. Methods:Analyses included patients receiving care in the Partners HealthCare System between January 1997 and December 2006, with a most recent CRP less than 3 years and more than 1 week before AMI. Over this period, 70,357 (487 HIV and 69,870 non-HIV) patients met these criteria, from the background population of 1,648,687 patients followed in the system. We included both CRP and high-sensitivity CRP and defined elevated CRP based on the normal range of the assay used. We used multivariate logistic regression analysis to test the association of elevated CRP and HIV with AMI after adjustment for demographic and other cardiovascular covariates, including hypertension, diabetes, and dyslipidemia. Results:In univariate analyses, elevated CRP and HIV were each significantly associated with AMI [odds ratio (OR) 2.51; 95% confidence interval (CI) 2.27 to 2.78; P < 0.0001 for elevated CRP and OR 2.07; 95% CI 1.31 to 3.10; P = 0.001 for HIV]. In a combined model including CRP category and HIV status, elevated CRP (OR 2.50; 95% CI 2.26 to 2.77; P < 0.0001) and HIV (OR 1.74; 95% CI 1.10 to 2.61; P = 0.01) were both independently associated with AMI. In a fully adjusted model controlling for age, sex, race, hypertension, diabetes, and dyslipidemia, both elevated CRP (OR 2.13; 95% CI 1.92 to 2.37; P < 0.0001) and HIV (OR 1.93; 95% CI 1.21 to 2.93; P = 0.004) remained independently associated with AMI. Compared with patients with normal CRP and without HIV, the OR for AMI was increased more than 4-fold among patients with HIV and elevated CRP. Conclusions:Elevated CRP and HIV are independently associated with increased AMI risk, and patients with HIV with increased CRP have a markedly increased relative risk of AMI. Measurement of CRP may be useful in the cardiovascular risk assessment of patients with HIV.

Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men.

Objective: The degree of subclinical coronary atherosclerosis in HIV-infected patients is unknown. We investigated the degree of subclinical atherosclerosis and the relationship of traditional and nontraditional risk factors to early atherosclerotic disease using coronary computed tomography angiography. Design and methods: Seventy-eight HIV-infected men (age 46.5 ± 6.5 years and duration of HIV 13.5 ± 6.1 years, CD4 T lymphocytes 523 ± 282; 81% undetectable viral load), and 32 HIV-negative men (age 45.4 ± 7.2 years) with similar demographic and coronary artery disease (CAD) risk factors, without history or symptoms of CAD, were prospectively recruited. 64-slice multidetector row computed tomography coronary angiography was performed to determine prevalence of coronary atherosclerosis, coronary stenosis, and quantitative plaque burden. Results: HIV-infected men demonstrated higher prevalence of coronary atherosclerosis than non-HIV-infected men (59 vs. 34%; P = 0.02), higher coronary plaque volume [55.9 (0–207.7); median (IQR) vs. 0 (0–80.5) μl; P = 0.02], greater number of coronary segments with plaque [1 (0–3) vs. 0 (0–1) segments; P = 0.03], and higher prevalence of Agatston calcium score more than 0 (46 vs. 25%, P = 0.04), despite similar Framingham 10-year risk for myocardial infarction, family history of CAD, and smoking status. Among HIV-infected patients, Framingham score, total cholesterol, low-density lipoprotein, CD4/CD8 ratio, and monocyte chemoattractant protein 1 were significantly associated with plaque burden. Duration of HIV infection was significantly associated with plaque volume (P = 0.002) and segments with plaque (P = 0.0009) and these relationships remained significant after adjustment for age, traditional risk factors, or duration of antiretroviral therapy. A total of 6.5% (95% confidence interval 2–15%) of our study population demonstrated angiographic evidence of obstructive CAD (>70% luminal narrowing) as compared with 0% in controls. Conclusion: Young, asymptomatic, HIV-infected men with long-standing HIV disease demonstrate an increased prevalence and degree of coronary atherosclerosis compared with non-HIV-infected patients. Both traditional and nontraditional risk factors contribute to atherosclerotic disease in HIV-infected patients.

Effects of Androgen Administration in Men with the AIDS Wasting Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial

The AIDS wasting syndrome is characterized by loss of lean body mass out of proportion to weight [1, 2]. The few effective treatments that have been identified are short-term pharmacologic agonists. Because loss of lean body mass is associated with decreased survival in men with the AIDS wasting syndrome [3], development of therapeutic strategies to increase lean body mass is of critical importance. Half of all men with AIDS are hypogonadal [4], and serum androgen levels correlate with lean body mass among hypogonadal men with the AIDS wasting syndrome [5]. Previous studies in non-HIV-infected hypogonadal men show that androgen administration has a significant anabolic effect on body composition [6-10]. We hypothesized that loss of the potent anabolic hormone testosterone in men with the AIDS wasting syndrome may contribute to the critical loss of lean body mass. Therefore, we investigated the effects of physiologic testosterone administration in men with the AIDS wasting syndrome. Methods Patients In 1995 and 1996, 51 HIV-positive men (42 8 years of age) were recruited from the multidisciplinary HIV practice at the Massachusetts General Hospital and from newspaper, television, and radio advertisements. Weight, testosterone levels, and medication history were determined at a screening assessment. To be included in the study, patients had to have decreased free testosterone levels, defined as less than 42 pmol/L at screening (normal range for men 18 to 49 years of age, 42 to 121 pmol/L [12.0 to 35.0 pg/mL]), and wasting, defined as weight less than 90% of ideal body weight or involuntary weight loss greater than 10% of baseline weight [11]. The CD4 count was not an inclusion criterion. We excluded patients with severe diarrhea (>6 stools/d); hemoglobin value less than 5.0 mmol/L (<8 g/dL); platelet count less than 50 000 cells/mm3; creatinine concentration greater than 177 mol/L (>2 mg/dL); new opportunistic infection within 6 weeks of screening; use of testosterone, anabolic steroids, growth hormone, ketoconazole, or systemic steroid therapy within 3 months before screening; or history of prostate cancer. In addition, patients receiving antiretroviral agents, including protease inhibitors, were required to be receiving a stable regimen for at least 6 weeks before study entry. Ten patients were receiving long-term, stable therapy with megestrol acetate for at least 8 weeks before study entry and were equally distributed between the two treatment groups (5 in the testosterone group and 5 in the placebo group). All patients gave written consent, and the study was approved by the Human Studies Committee of the Massachusetts General Hospital. Protocol Patients were randomly assigned to receive testosterone enanthate, 300 mg (Bio-Technology General Corp., Iselin, New Jersey), or placebo intramuscularly every 3 weeks by self-injection. Participants were stratified for weight less than or greater than 90% of ideal body weight and megestrol acetate use before randomization. Randomization was performed by the Massachusetts General Hospital Pharmacy by using a permuted block algorithm. The correspondence between patient code number and drug was generated by the study statistician; this list was available to the hospital pharmacist but not to the investigators or patients. The placebo contained sesame oil with chlorobutanol as a preservative and matched testosterone enanthate in color and consistency. The study drug was bottled by the Massachusetts General Hospital Pharmacy in containers labeled with the study name, expiration date, and patient code. Before the first injection, participants returned within approximately 2 weeks of the screening visit for a 3-day baseline inpatient visit to the General Clinical Research Center at the Massachusetts General Hospital for hormonal, nutritional, immune function, and body composition analysis, which included assessment by dual-energy x-ray absorptiometry, bioimpedance analysis, potassium-4040 K) isotope analysis, and measurement of urinary creatinine excretion. No patient experienced the onset of a new opportunistic infection, other complication, or substantial weight change between the screening and baseline visits. Patients were instructed on the proper technique for intramuscular injection; those who were unable to self-administer the study drug received injections every 3 weeks from the nursing staff of the General Clinical Research Center. Patients returned for an outpatient visit at 3 months for assessment of weight and determination of total-body potassium content and for a 3-day inpatient visit at 6 months; this visit was identical to the baseline evaluation. Patients also reported on response to therapy at the 6-month visit. Baseline data from 26 patients have been reported elsewhere [5]. Subsequent study visits were timed to correspond to the midpoint between study drug injections. Study drug compliance was confirmed by history, medication diaries, outpatient injection records, empty vial counts, and serum testosterone levels. History of medication use was assessed at each visit. The change in fat-free mass assessed by dual-energy x-ray absorptiometry was the primary clinical end point; changes in weight, muscle mass, total body potassium content, and quality of life were secondary end points. Body Composition Analysis Body composition was determined by four methods: 1) dual-energy x-ray absorptiometry to assess fat and fat-free mass (Hologic-2000 densitometer, Hologic, Inc., Waltham, Massachusetts; precision error, 3% for fat and 1.5% for fat-free mass [12], 2) 40K isotope analysis to assess total-body potassium content in a whole-body counter with sodium iodide detectors fixed above and below the patient at the xiphoid level (Canberra Nuclear, Meriden, Connecticut; precision error < 2.5% on the basis of repeated calibration with a known potassium chloride source [Appendix]), 3) urinary creatinine excretion averaged over 3 days (during which the patient received a meat-free diet) multiplied by a constant of 18 kg of muscle per gram of urinary creatinine and indexed for height to determine the percentage of predicted muscle mass [13, 14], and 4) bioimpedance analysis to determine total-body water content (Bioelectrical Impedance Analyzer Model BIA-101, RJL Systems, Clinton Turnpike, Michigan; correlation with deuterium oxide equivalent to R = 0.99 [15]). Lean body mass was derived from total-body potassium content by using the Equation of Forbes and Lewis of 68.1 mEq of potassium per kg of lean body mass [16]. Nutritional Assessment Weight was measured on the first day of each visit after an overnight fast. The percentage of ideal body weight was calculated on the basis of standard height and weight tables [17]. Patients were instructed on completion of a 4-day food record, which was analyzed for total calorie, fat, protein, and carbohydrate content (Minnesota Nutrition Data Systems, version 8A/2.6, Minneapolis, Minnesota) by the Clinical Research Center dietitian. Patients received an isocaloric, meat-free, protein-substituted diet 3 days before and during the inpatient assessments at baseline and at 6 months, during which creatinine excretion and nitrogen balance were measured. Total urinary nitrogen excretion was measured by the Kjeldal technique from consecutive 24-hour collections averaged over 3 days. Nonurinary nitrogen losses were assumed to be constant at 4 g/d [13, 18, 19]. Nitrogen intake was derived from total protein intake divided by a constant of 6.25 g of protein per g of nitrogen [19]. Calorie and protein intake were monitored on a daily basis and were modified to match the reports in the outpatient food records immediately before these visits. Resting energy expenditure was measured by indirect calorimetry with a metabolic cart. Energy requirements were calculated by using the Harris-Benedict equation [20]. Patient Reports of Response to Therapy Each patients perceived well-being was assessed at the end of the study by using nine linear analogue-scale questions on the overall treatment effect, change in quality of life, personal appearance, weight, and appetite (Table 1) [21]. A Karnofsky score was also determined at each visit. Table 1. Assessment of Patient Response to Therapy* Exercise Functional Testing Exercise history was assessed by a standardized questionnaire adapted from the study by Kohl and coworkers [22]. Exercise functional status was determined at the baseline and final visits by the physical therapy department of the Massachusetts General Hospital by using the 6-minute walk test, the timed sit-to-stand test, and the timed get-up-and-go test [23-25]. The distance covered in 6 minutes, the number of times the patient was able to move from a sitting to standing position in 10 seconds, and the time to cover a distance of 3 meters after standing from a seated position was recorded for each patient. Biochemical and Immunologic Assays Hematocrit and serum levels of follicle-stimulating hormone, luteinizing hormone, sex hormone-binding globulin, and prolactin were measured at the baseline and final visits by using published methods [26]. Serum levels of total and free testosterone were measured by radioimmunoassay kit (Diagnostics Products Corp., Los Angeles, California) with intra-assay coefficients of variation of 5% to 12% for total testosterone and 3.2% to 4.3% for free testosterone. CD4 cell counts were measured by flow cytometry (Becton Dickinson Immunocytochemistry Systems, San Jose, California). Viral burden was determined by using the Amplicor HIV-1 monitor test (Roche Molecular Systems, Branchburg, New Jersey). Statistical Analysis Sample size was based on the change in lean body mass in response to testosterone administration among adult men with acquired hypogonadism [8]. A change of 3.2% 4.0% was expected over 6 months. With 20 patients in each group, the study had an 80% chance of seeing an effect of testosterone at a two-sided