Quantifying the risks and benefits of efavirenz use in HIV‐infected women of childbearing age in the USA

Objectives

The aim of the study was to quantify the benefits (life expectancy gains) and risks (efavirenz‐related teratogenicity) associated with using efavirenz in HIV‐infected women of childbearing age in the USA.

Methods

We used data from the Women's Interagency HIV Study in an HIV disease simulation model to estimate life expectancy in women who receive an efavirenz‐based initial antiretroviral regimen compared with those who delay efavirenz use and receive a boosted protease inhibitor‐based initial regimen. To estimate excess risk of teratogenic events with and without efavirenz exposure per 100 000 women, we incorporated literature‐based rates of pregnancy, live births, and teratogenic events into a decision analytic model. We assumed a teratogenicity risk of 2.90 events/100 live births in women exposed to efavirenz during pregnancy and 2.68/100 live births in unexposed women.

Results

Survival for HIV‐infected women who received an efavirenz‐based initial antiretroviral therapy (ART) regimen was 0.89 years greater than for women receiving non‐efavirenz‐based initial therapy (28.91 vs. 28.02 years). The rate of teratogenic events was 77.26/100 000 exposed women, compared with 72.46/100 000 unexposed women. Survival estimates were sensitive to variations in treatment efficacy and AIDS‐related mortality. Estimates of excess teratogenic events were most sensitive to pregnancy rates and number of teratogenic events/100 live births in efavirenz‐exposed women.

Conclusions

Use of non‐efavirenz‐based initial ART in HIV‐infected women of childbearing age may reduce life expectancy gains from antiretroviral treatment, but may also prevent teratogenic events. Decision‐making regarding efavirenz use presents a trade‐off between these two risks; this study can inform discussions between patients and health care providers.     

Glucagon Supports Postabsorptive Plasma Glucose Concentrations in Humans With Biologically Optimal Insulin Levels

OBJECTIVE

Based on the premise that postabsorptive patients with type 1 diabetes receiving intravenous insulin in a dose that maintains stable euglycemia are receiving biologically optimal insulin replacement, we tested the hypothesis that glucagon supports postabsorptive plasma glucose concentrations in humans.

RESEARCH DESIGN AND METHODS

Fourteen patients with type 1 diabetes were studied after an overnight fast on up to five occasions. Insulin was infused intravenously to hold plasma glucose concentrations at ∼100 mg/dl (5.6 mmol/l) overnight and fixed from −60 to 240 min the following morning. From 0 through 180 min the patients also received 1) saline, 2) octreotide 30 ng · kg⁻¹ · min⁻¹ with growth hormone replacement or octreotide with growth hormone, plus 3) glucagon in doses of 0.5 ng · kg⁻¹ · min⁻¹, 4) 1.0 ng · kg⁻¹ · min⁻¹, and 5) 2.0 ng · kg⁻¹ · min⁻¹.

RESULTS

Compared with a mean ± SE of 98 ± 5 mg/dl (5.4 ± 0.3 mmol/l) at 180 min during saline, mean plasma glucose concentrations declined to 58 ± 1 mg/dl (3.2 ± 0.1 mmol/l) (P < 0.001) at 180 min during octreotide plus saline and were 104 ± 16 mg/dl (5.8 ± 0.9 mmol/l) (NS), 143 ± 13 mg/dl (7.9 ± 0.7 mmol/l) (P = 0.004), and 160 ± 15 mg/dl (8.9 ± 0.8 mmol/l) (P < 0.001) at 180 min during octreotide plus glucagon in doses of 0.5, 1.0, and 2.0 ng · kg⁻¹ · min⁻¹, respectively.

CONCLUSIONS

In the setting of biologically optimal insulin replacement, suppression of glucagon secretion with octreotide caused a progressive fall in plasma glucose concentrations that was prevented by glucagon replacement. These data document that glucagon supports postabsorptive glucose concentrations in humans.The current interest in the development of drugs that block the action or secretion of glucagon for the treatment of diabetes rests on the premise that glucagon supports the plasma glucose concentration and, therefore, that glucagon, in concert with insulin deficiency, may play a role in the pathogenesis of hyperglycemia in diabetes (1–4). That premise is based largely on studies with somatostatin including those with the pancreatic clamp technique (4,5). That technique involves infusion of somatostatin (or of the somatostatin analog octreotide) (6), which suppresses insulin and glucagon secretion among other actions, alone and with insulin replacement, glucagon replacement, and both insulin and glucagon replacement to document the roles of suppression of those hormones in the changes in glycemia (or in glucose kinetics when glucose concentrations are clamped) that result from administration of somatostatin (7–10).Obviously, the biological appropriateness of the putative replacement doses of insulin and glucagon are critical to the interpretation of pancreatic clamp data (11,12). Excessive insulin replacement (or insufficient glucagon replacement) would confound the data. Insulin has been infused peripherally in doses of 0.14 (13), 0.15 (7), 0.20 (14), and 0.24 (15) mU · kg⁻¹ · min⁻¹ in humans to replace basal insulin levels during infusion of somatostatin. However, we found that intravenous insulin doses as low as 0.15 mU · kg⁻¹ · min⁻¹ are excessive; when infused alone in healthy humans they drove plasma glucose concentrations down to subnormal levels and thus activated glucose counterregulatory systems (nearly complete suppression of insulin secretion and stimulation of glucagon and epinephrine secretion) (11). Although it also lowered plasma glucose concentrations, insulin infused in a dose of 0.10 mU · kg⁻¹ · min⁻¹ did not drive glucose down to subnormal levels and therefore did not activate glucose counterregulatory systems, at least over 2 h (11). Accordingly, we used the latter lower insulin replacement dose in additional pancreatic clamp studies in healthy adults (12). Octreotide infusion caused plasma glucose concentrations to decrease and then increase as expected (6–10); octreotide plus insulin in a dose of 0.10 mU · kg⁻¹ · min⁻¹ caused a sustained decrease in plasma glucose consistent with the interpretation that glucagon, in concert with insulin, supports the postabsorptive plasma glucose concentration. However, the addition of glucagon in a dose of 1.0 ng · kg⁻¹ · min⁻¹, a putative replacement dose (16), to octreotide and insulin did not raise glucose levels to those observed during infusion of octreotide alone. Therefore, the insulin dose was still too high, the glucagon dose was too low, or both.To clarify this issue, we tested the hypothesis that glucagon supports the postabsorptive plasma glucose concentration in insulin-sufficient patients with type 1 diabetes. Our premise is that demonstrably endogenous insulin-deficient patients with type 1 diabetes infused intravenously with insulin in a dose that maintains stable euglycemia are receiving a biologically optimal insulin replacement dose.     

Direct alpha-adrenergic stimulation of hepatic glucose production in human subjects

Six normal humans each underwent infusions of 1) saline; 2) propranolol; 3) somatostatin; 4) somatostatin with propranolol; and 5) somatostatin with propranolol plus phentolamine on separate occasions. Propranolol alone had no effect on glucose production or plasma glucose. Somatostatin alone produced the expected initial decrease followed by an increase in both hepatic glucose production and plasma glucose. beta-Adrenergic blockade with propranolol displaced the glucose production (MANOVA, P = 0.0220) and plasma glucose (MANOVA, P = 0.0057) somatostatin response curves to higher levels, whereas alpha-adrenergic blockade with phentolamine combined with beta-adrenergic blockade displaced the glucose production (MANOVA, P = 0.0281) and plasma glucose (MANOVA, P = 0.0134) somatostatin response curves to lower levels. Because plasma insulin, C-peptide, and glucagon were suppressed comparably under all three conditions and plasma glucose concentrations were comparable initially, this represents direct alpha-adrenergic stimulation of hepatic glucose production in postabsorptive humans demonstrable when the primary glucoregulatory hormones are withdrawn and beta-adrenergic mechanisms are blocked. It is best attributed to sympathetic neural norepinephrine release.     

Identification of type I diabetic patients at increased risk for hypoglycemia during intensive therapy

During intravenous insulin infusions (40 mU per kilogram of body weight per hour for up to 100 minutes), 9 of 22 patients with insulin-requiring diabetes mellitus had neurologic signs or symptoms of hypoglycemia, plasma glucose concentrations that were below 35 mg per deciliter (1.9 mmol per liter) and continued to decline, or both. This inadequate glucose counterregulation resulted from the combined effect of deficient glucagon and epinephrine responses. In 8 of the 9 patients with inadequate counterregulation severe hypoglycemia developed during subsequent intensive therapy, whereas such episodes occurred in only 1 of 13 patients with adequate counterregulation. Thus, an intravenous insulin-infusion test can prospectively identify patients who are at increased risk for recurrent severe hypoglycemia during intensive therapy for diabetes.     

Do centimetres matter? Self‐reported versus estimated height measurements in parents

Aim: An impressive discrepancy between reported and measured parental height is often observed. The aims of this study were: (a) to assess whether there is a significant difference between the reported and measured parental height; (b) to focus on the reported and, thereafter, measured height of the partner; (c) to analyse its impact on the calculated target height range. Methods/Results: A total of 1542 individual parents were enrolled. The parents were subdivided into three groups: normal height (3–97th Centile), short (<3%) and tall (>97%) stature. Overall, compared with men, women were far better in estimating their own height (p < 0.001). Where both partners were of normal, short or tall stature, the estimated heights of their partner were quite accurate. Women of normal stature underestimated the short partner and overestimated the tall partner, whereas male partners of normal stature overestimated both their short as well as tall partners. Women of tall stature estimated the heights of their short partners correctly, whereas heights of normal statured men were underestimated. On the other hand, tall men overestimated the heights of their female partners who are of normal and short stature. Furthermore, women of short stature estimated the partners of normal stature adequately, and the heights of their tall partners were overestimated. Interestingly, the short men significantly underestimated the normal, but overestimated tall female partners. Conclusion: Only measured heights should be used to perform accurate evaluations of height, particularly when diagnostic tests or treatment interventions are contemplated. For clinical trails, we suggest that only quality measured parental heights are acceptable, as the errors incurred in estimates may enhance/conceal true treatment effects.