It is generally assumed that most, of not all, of the protein-anabolic effects of rhGH are mediated by IGF-1 (50). Indeed, as described earlier, significant increases in plasma levels of IGF-1 have been observed following rhGH administration to patients with HIV-associated wasting (30,39). However, the magnitude of these increases is less than that seen in HIV-negative controls. These observations have prompted speculation that there may be a degree of rhGH resistance in patients with HIV-associated wasting and that IGF-1 may be a more effective treatment than GH. Previously, in healthy humans consuming hypocaloric diets, administration of recombinant human IGF-1 (rhIGF-1) resulted in significant improvement in nitrogen balance (51,52).
In a metabolic ward study in patients with HIV associated wasting fed a weight-maintaining diet, daily infusions of rhIGF-1 (4 ^g/kg/h for 12 h) produced significant short-term retention of nitrogen, averaging approx 1.7 g/d (39). However, a waning effect was noted after 9 d of therapy. Notably, infusion of a higher dose of rhIGF-1 (12 ^g/kg/h for 12 h) produced no significant nitrogen retention. This reverse dose-response relationship may have resulted from the suppression of IGF binding protein-3 (IGFBP-3) in patients given the higher dose, reducing thereby the bioavailability of the exogenous rhIGF-1. Leucine and glycine flux, measured by stable isotope techniques, were unaffected by treatment at either dosing level. The predominant side effect of this treatment was headache, which occurred in 10 of 13 subjects treated.
Preliminary studies have also been performed to identify the optimal subcutaneous dosing regimen for rhIGF-1 (53). First, an HIV-negative subject was treated with increasing doses of rhIGF-1 for a total of 23 d. Because a tendency to hypoglycemia occurred at doses greater than 90 ^g/kg/d, that dose was chosen for subsequent studies. In one HIV-negative and one HIV-positive subject who received a constant dose of 90 ^g/kg/d, given as a single subcutaneous injection for 14 d, decreases in urine urea nitrogen excretion averaging +1.6 and +3.4 g/d in the HIV-negative and HIV-positive patient, respectively, were observed during the entire treatment period. Thus, there was no evidence of the tachyphylaxis reported to occur during IV infusion of rhIGF-1 in a study in HIV-positive subjects (39). Interestingly, increases in REE also occurred in a dose-dependent manner, and increases in lipid oxidation rates were observed in all three patients given rhIGF-1 (53).
Overall, the nitrogen-retaining effects of rhIGF-1 in metabolic ward studies did not consistently attain levels seen with rhGH (30), whereas the increases in REE were comparable to those seen with rhGH. Moreover, the insulin-like effect of IGF-1 poses a potential obstacle to its use in patients with HIV-associated wasting, many of whom may be at increased risk of hypoglycemia because of limited energy stores, anorexia, malabsorption, or increased insulin sensitivity (54,55).
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