Implementation of the INTERGROWTH-21st Project in the United States.

The North American site in the INTERGROWTH-21(st) Project was North Seattle, Washington State, USA. The majority of the data were collected from within Seattle City, which has approximately 12 300 births per year. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from two hospitals (Swedish Medical Center and the University of Washington) covering almost 80% of deliveries within the target population. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from several antenatal clinics serving the University of Washington Medical Center and Providence Everett Medical Center. Special activities to encourage participation and raise awareness of the studies included furnishing the recruitment sites with fliers designed by the Project Coordinating Unit, and presenting the studies to clinical staff to encourage providers to refer appropriate patients. One of the major challenges at this site was the low recruitment rate in the early phase of the FGLS because of the high rates of smoking, maternal age >35 years and body mass index >30 years. This was remedied by the inclusion of other ancillary clinics, as well as increased advertising among the general public.

Altered fat distribution in HIV-positive men on nucleoside analog reverse transcriptase inhibitor therapy.

To determine whether HIV infection, the wasting syndrome, or nucleoside analog reverse transcriptase inhibitor (NRTI) or protease inhibitor (PI) therapy uniquely affect fat distribution in men, we performed manual regional analysis of total, appendicular, trunk, and central abdominal fat measured by dual-energy X-ray absorptiometry (DEXA). Five groups of study subjects were identified for this cross-sectional analysis: HIV-negative controls (HIV-; N = 44) and four groups of HIV-positive subjects: antiretroviral (ARV)-naive or with limited prior use of NRTIs (ARV-; N = 23); on NRTIs for > or =6 months but PI-naive (NRTI; N = 30); on an NRTI/PI regimen for > or =6 months but with no complaints of abnormal fat distribution (NRTI/PI; N = 26); and those on NRTIs but PI-naive with the wasting syndrome (NRTI/WS; N = 40). Total, appendicular, trunk, and central abdominal fat was significantly lower in NRTI/WS. The ratio of trunk fat to appendicular fat was virtually identical in HIV- and ARV-. This ratio was significantly higher in the NRTI, NRTI/PI, and NRTI/WS groups, and values in these three groups were similar. These cross-sectional data suggest that HIV-infected men receiving NRTIs have an altered pattern of fat distribution, compared with HIV-negative men and HIV-positive men who are not receiving antiretroviral therapy. This effect was independent of the concomitant use of a PI or a diagnosis of the wasting syndrome. We saw no evidence of a unique effect of HIV infection per se on regional fat distribution. Although the fat ratio is increasingly employed, its physiologic significance is unclear. Our results, which have been obtained retrospectively, are intended to provide the impetus for prospective, controlled studies of the interactions among drug and host factors in the development of fat distribution abnormalities.

Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection.

Although protease inhibitor (PI) therapy has improved the clinical status of patients with HIV infection, concerns have arisen that such treatment may have deleterious effects on glucose control, lipid metabolism, and body fat distribution. To determine whether initiation of PI therapy uniquely affects glucose and lipid metabolism, we analyzed paired data in HIV-infected patients before and after beginning antiretroviral therapy that included a PI (PI; N = 20) or lamivudine (3TC) but no PI (3TC; N = 9); and a control group on stable regimens that included neither of these agents (CONT: N = 12). Measurements included fasting glucose; insulin; triglycerides; total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol; HIV RNA; CD4+ lymphocytes; weight; and total and regional body composition. Neither weight nor total or regional fat content changed significantly in any group during the period of observation. Nonetheless, in patients beginning PI therapy, there were significant increases in glucose (+9+/-3 mg/dl; p = .0136), insulin (+12.2+/-4.9 U/ml; p = .023), triglycerides (+53+/-17 mg/dl; p = .0069), and total and LDL cholesterol (+32+/-11 and +18+/-5 mg/dl; p = .0082 and .0026, respectively). None of these parameters changed significantly in the 3TC or CONT groups. The PI and 3TC groups experienced comparable increases in CD4+ lymphocytes, suggesting that the observed metabolic effects may be associated with PIs uniquely, rather than improvement in clinical status. However, it is also possible that the metabolic effects of PIs are associated with more effective viral suppression, because a greater proportion of patients in the PI group achieved undetectable levels of virus. We conclude that changes in glucose and lipid metabolism are induced by PI therapy in the absence of significant changes in weight or fat distribution. Longer periods of follow-up will be required to determine the clinical significance of these changes. However, at the moment, the risks associated with these metabolic effects do not appear to outweigh improvements in survival seen with PI therapy.

"Buffalo hump" in men with HIV-1 infection.

BACKGROUND: Enlargement of the dorsocervical fat pad ("buffalo hump") has been reported in numerous HIV-1-infected patients. Some investigators have speculated that this finding is associated with protease-inhibitor treatment. METHODS: Between June, 1995, and October, 1997, we studied eight HIV-1-infected men who had developed a buffalo hump while otherwise stable on antiretroviral therapy. Measurement of 24 h urinary free cortisol excretion and an overnight low-dose dexamethasone suppression test were done to screen for Cushing's syndrome. In one patient, plasma cortisol concentrations were measured every 4 h for 24 h to assess the circadian rhythm of cortisol. Results of total and regional body-composition analysis by dual-energy X-ray absorptiometry, and glucose, cholesterol, triglyceride, and cortisol concentrations were compared with those obtained in a control population of 15 HIV-1-positive men whose age, body-mass index (BMI), and CD4-lymphocyte count were within the range of values in the eight study patients. FINDINGS: The eight patients with a buffalo hump were clinically stable on various antiretroviral regimens, four of which included a protease inhibitor. No other signs of Cushing's syndrome were observed, and plasma cortisol values did not differ significantly from those of controls. 24 h urinary free cortisol excretion was normal in seven patients and slightly raised in one (248 nmoles). In this patient, a repeat 24 h urinary free cortisol was 175 nmoles and plasma cortisol concentrations over 24 h showed a normal circadian pattern (nadir 83 nmol/L at 2400 h). All eight patients had normal suppression of cortisol values after dexamethasone 1 mg (plasma cortisol less than 83 nmol/L). When compared with HIV-1-positive controls, men with a buffalo hump had a significantly greater proportion of fat in the trunk region, suggesting central fat accumulation. Triglyceride but not cholesterol values were higher in the patients than in controls but this difference was not significant. Fasting glucose values did not differ significantly. INTERPRETATION: The development of a buffalo hump cannot be attributed to hypercortisolism in these eight men. Furthermore, its occurrence is not unique to patients on protease inhibitors. Although the mechanism for dorsocervical fat accumulation is unclear, we speculate that regional abnormalities in lipogenesis and lipolysis occur, possibly influenced by the hormonal and metabolic changes seen with HIV-1 infection and its treatment.