Birgitte R. Hansen

The prevalence of metabolic syndrome in Danish patients with HIV infection: the effect of antiretroviral therapy

The prevalence of metabolic syndrome (MS) in HIV‐infected patients on highly active antiretroviral therapy (HAART) is a subject of debate. We investigated the prevalence of MS in a cohort of Danish HIV‐infected patients and estimated the effect of the various classes of antiretroviral therapies on the prevalence of MS and its components.

Impact of switching antiretroviral therapy on lipodystrophy and other metabolic complications: a review

Following the introduction of highly active antiretroviral therapy (HAART), metabolic and morphological complications known as HIV associated lipodystrophy syndrome (HALS) have been increasingly common. The approaches to target these complications span from resistance exercise, diet and use of the antidiabetics metformin or glitazones to high dose recombinant human growth hormone therapy or switching antiretroviral regimen. When looking at the effect of switching therapy, focus has been addressed to protease inhibitor (PI) based regimens, as PI was the first component of HAART recognized to be correlated with the disfiguring body-alterations known as HALS. More recently, however, regimens containing nucleoside reverse-transcriptase inhibitors (NRTI) have attracted attention. Reviewing switch studies regarding metabolic parameters and body shape changes, certain trends emerge. Switching from PI, the metabolic complications such as dyslipidaemia and insulin resistance seem to be partly reversible, whereas the morphologic alterations appear to be unchanged. In studies in which NRTIs are switched, dyslipidaemia appears unaffected, but a modest improvement in peripheral lipoatrophy has been reported. However the results are often inconsistent and difficult to interpret, mostly because of limitations in study design, patient number and duration of follow-up. The need for larger, controlled, randomized, long-term studies is evident.

Improved thymic index, density and output in HIV-infected patients following low-dose growth hormone therapy: a placebo controlled study.

Objectives:To investigate the effect of low-dose, long-term recombinant human growth hormone (rhGH) therapy on immune reconstitution in human immunodeficiency virus (HIV)-infected patients with focus on thymic index, density and output. Design:Randomized, placebo-controlled, double-blind, single-centre trial. Methods:Forty-six HIV-infected Caucasian men on highly active antiretroviral therapy, 21–60 years of age, were included. Twenty-eight patients were randomized to 0.7mg/day rhGH and 18 patients to placebo, administrated as daily subcutaneous injections between 1300 and 1500 h for 40 weeks. Endpoints were changes from baseline in thymic size and thymic output measured as T-cell receptor rearrangement excision circles (TREC) frequency and total TREC content, and total and naive CD4+ cells. Results:Thymic density and thymic index increased in the GH group, compared with the placebo group (28 versus 4 Hounsfield units, P = 0.006 and 1 versus 0, P = 0.004). TREC frequency and total TREC content increased in the GH group, compared with the placebo group (37 versus −8%, P = 0.049 and 51 versus –14%, P = 0.026). Total CD4+ cells and naive CD4+ cells increased insignificantly more in the GH than the placebo group [11.4%, 95% confidence interval (CI) −6.0 to 28.9; P = 0.19 and 18%, interquartile range (IQR) −4, 40 versus 13%, IQR −12, 39; P = 0.79]. Therapy was well tolerated. Conclusions:Daily treatment with a low dose rhGH of 0.7 mg for 40 weeks stimulated thymopoiesis expressed by thymic index, density and area, TREC frequency and total TREC content in CD4+ cells in HIV-infected patients on highly active antiretroviral therapy.

Different growth hormone sensitivity of target tissues and growth hormone response to glucose in HIV-infected patients with and without lipodystrophy

Growth hormone (GH)-secretion in HIV-lipodystrophy is impaired; however, GH-sensitivity of GH-target tissues remains to be evaluated. We measured overnight fasting concentrations of GH-sensitive insulin-like growth-factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) including GH binding protein (GHBP), a marker of GH-receptor sensitivity, in antiretroviral treated HIV-infected patients with (LIPO) and without lipodystrophy (NONLIPO) and antiretroviral naïve HIV-infected patients (NAÏVE). Three h GH-suppression tests using oral glucose were undertaken to determine dynamics of GH-secretion. IGF-I and IGFBP-3 were increased in LIPO compared with NONLIPO (p<0.05), but did not differ significantly between NONLIPO and NAÏVE. Area under the curve of GH (AUC-GH) during the GH-suppression test was decreased in LIPO compared with NONLIPO (p<0.05). Ratio of limb to trunk fat, which was decreased in LIPO compared to NONLIPO and NAÏVE (p<0.001), correlated positively with AUC-GH and rebound-GH (p<0.05). All groups displayed suppression of GH during the suppression test (p<0.05) and all groups, except LIPO, displayed a rebound of GH (p<0.05), which probably is explained by persistently increased plasma glucose in LIPO compared with NONLIPO and NAÏVE (p<0.01). GHBP was inversely correlated with AUC-GH (p<0.01). Our data suggest that GH-target tissues in LIPO are at least as GH-sensitive as in HIV-infected patients without lipodystrophy.

When should densitometry be repeated in healthy peri- and postmenopausal women: the Danish osteoporosis prevention study.

Intervention should be considered in postmenopausal women with bone mineral density (BMD) ≥1 SD below the reference (T or Z score < −1). However, it is unclear when densitometry should be repeated. This study aimed at determining the need for repeat DXA within 5 years in untreated peri‐/postmenopausal women to detect declines of T or Z score to below −1 with 85% confidence. A cohort of 925 healthy women (aged 51.2 ± 2.9 years) were followed within the Danish Osteoporosis Prevention Study (DOPS) for 5 years without hormone‐replacement therapy (HRT). DXA of spine, hip, and forearm was done at 0,1, 2, 3, and 5 years (Hologic QDR‐1000/2000). The annual loss in SD units was 0.12 ± 0.10 at the spine (1.3%), 0.10 ± 0.09 at the femoral neck (1.2%), and 0.07 ± 0.09 at the ultradistal (UD) forearm (1.0%). Accordingly, T scores below −1 developed earlier at the spine. The need for a future DXA scan to predict declines of T and Z scores below −1 depended strongly on baseline BMD. In subjects with a positive T score, the risk of developing T < −1 remained at <15% for 5 years at all measured sites. A new scan was needed after 1 year if the T score was below −0.5, and after 3 years if the T score was between 0 and −0.5. Slightly longer intervals apply if Z scores are used. Follow‐up densitometry in untreated women should be individually targeted from baseline BMD rather than scheduled at fixed time intervals. An algorithm for planning repeat densitometry in perimenopausal women is provided.

Long-term high-physiological-dose growth hormone reduces intra-abdominal fat in HIV-infected patients with a neutral effect on glucose metabolism.

The aim of the study was to investigate the effect of long‐term high‐physiological‐dose recombinant human growth hormone (rhGH) therapy on fat distribution and glucose metabolism in HIV‐infected patients.

Comparison of Quantitative Ultrasound and Dual X-Ray Absorptiometry in Estrogen-Treated Early Postmenopausal Women

Identifying individuals at risk of developing osteoporosis is important in order to initiate early treatment. Many new techniques have been proposed as alternatives for DXA-scanning. Some of these alternatives certainly have advantages, but none have so far been demonstrated to predict fractures better, or even to identify individuals at risk of osteoporosis as well as with the standard method. In this study, comprising a group of women from the Danish Osteoporosis Prevention Study, we wished to investigate whether a technique based on quantitative ultrasound (QUS) could identify individuals with low BMC/BMD as measured by dual X-ray absorptiometry (DXA). Furthermore, we wished to test whether the method could detect differences between untreated individuals and those treated with hormone replacement therapy. We found that QUS could detect differences between the treated and untreated groups, but it was unable to identify women with low BMD, although it might be able to identify persons not at risk of osteoporosis. Low QUS values should be followed by a regular DXA measurement to confirm the presence of osteoporosis.

Circulating sex hormones and gene expression of subcutaneous adipose tissue oestrogen and alpha-adrenergic receptors in HIV-lipodystrophy: implications for fat distribution

Objective  Circulating oestradiol and testosterone, which have been shown to increase in human immunodeficiency virus (HIV)‐infected patients following highly active antiretroviral therapy (HAART), may influence fat distribution and insulin sensitivity. Oestradiol increases subcutaneous adipose tissue in humans possibly through binding to oestrogen‐receptor‐α, which in turn activates anti‐lipolytic α2A‐adrenergic‐receptor.

Sustained low-dose growth hormone therapy optimizes bioactive insulin-like growth factor-I level and may enhance CD4 T-cell number in HIV infection.

High‐dose recombinant human growth hormone (rhGH) (2–6 mg/day) regimes may facilitate T‐cell restoration in patients infected with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART). However, high‐dose rhGH regimens increase insulin‐like growth factor‐I (IGF‐I) to supra‐physiological levels associated with severe side effects. The present study investigated whether lower doses of rhGH may improve T‐cell restoration in patients infected with HIV following an expedient response of total and bioactive (i.e., free) IGF‐I. A previous 16‐week pilot‐study included six HIV‐infected patients on stable HAART to receive rhGH 0.7 mg/day, which increased total (+117%, P < 0.01) and free (+155%, P < 0.01) IGF‐I levels. The study was extended to examine whether continuous use of low‐dose rhGH (0.7 mg/day until week 60; 0.4 mg/day from week 60 to week 140) would maintain expedient IGF‐I levels and improve CD4 T‐cell response. Total and free IGF‐I increased at week 36 (+97%, P < 0.01 and +125%, P < 0.01, respectively) and week 60 (+77%, P = 0.01 and +125%, P < 0.01) compared to baseline levels (161 ± 15 and 0.75 ± 0.11 µg/L). CD4 T‐cell number increased at week 36 (+15%, P < 0.05) and week 60 (+31%, P = 0.01) compared to baseline levels (456 ± 55 cells/µL). Following rhGH dose reduction, total IGF‐I and CD4 T‐cell number remained increased at week 88 (+44%, P = 0.01 and +33%, P < 0.01) and week 140 (+46%, P = 0.07 and +36%, P = 0.02) compared to baseline levels. These data support the notion that low‐dose rhGH regimens may increase expediently total and bioactive IGF‐I and improve T‐cell restoration in patients infected with HIV on HAART. J. Med. Virol. 82:197–205, 2010.

Low-dose growth hormone therapy reduces inflammation in HIV-infected patients: a randomized placebo-controlled study

Abstract Background: Combination antiretroviral therapy (cART) has drastically increased the life expectancy of HIV-infected patients. However, HIV-infected patients exhibit increased inflammation and 33–58% exhibit a characteristic fat re-distribution termed HIV-associated lipodystrophy syndrome (HALS). Recombinant human growth hormone (rhGH) has been tested as treatment of HALS. Low-dose rhGH therapy improves thymopoiesis and fat distribution in HIV-infected patients and appears to be well tolerated. However, since high-dose rhGH is associated with adverse events related to inflammation, we wanted to investigate the impact of low-dose rhGH therapy on inflammation in HIV-infected patients. Methods: Forty-six cART-treated HIV-infected men were included in the HIV-GH low-dose (HIGH/Low) study: a randomized, placebo-controlled, double-blinded trial. Subjects were randomized 3:2 to 0.7 mg/day rhGH, or placebo for 40 weeks. rhGH was self-administered between 1 pm and 3 pm. The primary outcome of this substudy was changes in inflammation measured by plasma C-reactive protein (CRP) and soluble urokinase plasminogen activator receptor (suPAR). Results: Both CRP (−66%, p = 0.002) and suPAR (−9.7%, p = 0.06) decreased in the rhGH group compared to placebo; however, only CRP decreased significantly. The effect of rhGH on inflammation was not mediated through rhGH-induced changes in insulin-like growth factor 1, body composition, or immune parameters. Conclusion: Daily 0.7 mg rhGH treatment for 40 weeks, administered at nadir endogenous GH secretion, significantly reduced CRP. The effect does not appear to be mediated by other factors. Our findings suggest that low-dose rhGH treatment may minimize long-term risks associated with high-dose rhGH therapy.