Bone loss in patients with HIV infection.

The prognosis of HIV infection has been considerably improved by the introduction of antiretroviral drugs. However, the longer survival times are associated with the emergence of new complications including decreased bone mineral density (BMD) values and/or bone insufficiency fractures. A meta-analysis of studies published between 1966 and 2005 showed bone absorptiometry results indicating osteoporosis in 15% of HIV patients and osteopenia in 52%. Longitudinal studies found no evidence that antiretroviral drug therapy contributed to the occurrence of bone loss. Available data indicate uncoupling with increases in bone resorption markers and decreases in bone formation markers. In addition to conventional risk factors for osteoporotic fractures, factors in HIV-infected patients may include malnutrition (wasting syndrome), hypogonadism, disorders in calcium and phosphate metabolism, and HIV infection per se. In patients with established bone insufficiency, bisphosphonate therapy should be considered. Alendronate in combination with vitamin D and calcium supplementation has been found effective in improving BMD values.

Novel approaches to the treatment of cachexia.

Cachexia is a complex syndrome. The main components of this pathological state are anorexia and metabolic abnormalities, such as glucose intolerance, fat depletion and muscle protein catabolism among others. The aim of the present article is to review the recent therapeutic approaches that have been designed to fight and counteract muscle wasting in different pathological states such as cancer, AIDS and chronic heart failure.

Spotlight on mammalian cell-derived somatropin in HIV-associated wasting.

HIV-associated wasting, characterized by progressive loss of lean body mass and bodyweight, remains a significant problem in the era of highly active antiretroviral therapy. Loss of body cell mass, a component of lean body mass, is associated with decreased survival. Somatropin (recombinant human growth hormone) derived from mammalian cells (Serostim) is the only US FDA-approved treatment indicated to increase lean body mass, bodyweight, and physical endurance in HIV-associated wasting. Somatropin 0.1 mg/kg/day administered subcutaneously for 12 weeks effectively increased work output, bodyweight, and lean body mass, and improved health-related quality of life, compared with placebo, and had a generally manageable tolerability profile in a large randomized study in patients with HIV-associated wasting. Potential areas for further research include determination of longer-term efficacy and tolerability, the cost effectiveness of treatment, the optimal somatropin dosage, management of patients after 12 weeks' therapy, and whether maintenance strategies might exist to maintain accrued lean body mass with lower doses of somatropin. Nevertheless, indications to date are that somatropin is likely to have an important role in the treatment of patients with HIV-associated wasting.

Mammalian cell-derived somatropin : a review of its use in the management of HIV-associated wasting.

HIV-associated wasting, characterised by progressive loss of lean body mass and bodyweight, remains a significant problem in the era of highly active antiretroviral therapy (HAART). Loss of body cell mass, a component of lean body mass, is associated with decreased survival. Somatropin (recombinant human growth hormone) derived from mammalian cells (Serostim) is the only US FDA-approved treatment indicated to increase lean body mass, bodyweight and physical endurance in HIV-associated wasting. Somatropin 0.1 mg/kg/day administered subcutaneously for 12 weeks effectively increased work output, bodyweight and lean body mass and improved health-related quality of life (HR-QOL), compared with placebo, and had a generally manageable tolerability profile in a large randomised study in patients with HIV-associated wasting. Potential areas for further research include determination of longer-term efficacy and tolerability, the cost effectiveness of treatment, the optimal somatropin dosage, management of patients after 12 weeks' therapy and whether maintenance strategies might exist to maintain accrued lean body mass with lower doses of somatropin. Nevertheless, indications to date are that somatropin is likely to have an important role in the treatment of patients with HIV-associated wasting.

Recombinant human growth hormone therapy in HIV-associated wasting and visceral adiposity.

This article reviews the clinical data on recombinant human growth hormone therapy of body composition abnormalities in HIV-infected patients. Short-term recombinant human growth hormone therapy at pharmacologic doses modestly increases total body weight and lean body mass in patients with HIV wasting, resulting in improvements in physical capacity and quality of life. Short-term recombinant human growth hormone therapy has a clear dose-dependent impact on trunk and visceral fat in HIV-infected patients with central fat accumulation, resulting in improvements in perception of body image and a beneficial effect on lipid parameters. Recombinant human growth hormone therapy is also accompanied by dose-dependent side effects related to fluid retention and increased insulin resistance. The optimal treatment strategy, maintenance dose and duration of treatment have not been identified.

Growth hormone treatment improves peripheral muscle oxygen extraction-utilization during exercise in patients with human immunodeficiency virus-associated wasting: a randomized controlled trial.

The arteriovenous oxygen difference (a-vO(2) difference), a measure of peripheral muscle oxygen extraction-utilization during exercise, is reduced in antiretroviral-treated patients with human immunodeficiency virus (HIV), thus causing a shift in the cardiac output-oxygen consumption (Q-VO(2)) relationship. We investigated the impact of recombinant human GH (rhGH) treatment on a-vO(2) difference and the Q-VO(2) relationship during submaximal exercise by randomizing 12 HIV-infected patients (mean +/- sem: age, 43.3 +/- 1.5 yr; body mass, 69.5 +/- 2.9 kg; body mass index, 22.4 +/- 0.9 kg/m(2); maximum oxygen consumption, 33.6 +/- 1.5 ml/kg x min), with documented unintentional weight loss (>or=10% within the preceding 12 months) despite antiretroviral therapy, to receive 3 months of rhGH (6 mg/d) in a double-blind, placebo-controlled, cross-over trial. We assessed Q (determined noninvasively using CO(2) rebreathing), and subsequently a-vO(2) difference, from Q-VO(2) relationships. At study entry, the mean slope (8.1 +/- 1.0 liters/min x 1-liter increase in VO(2)) and intercept (3.1 +/- 1.3 liters/min), generated from each patient's Q-VO(2) relationship, were greater and lower, respectively, than those reported for healthy individuals (6.0 and 4.0, respectively), thereby indicating a deficit in the a-vO(2) difference. After 3 months of rhGH treatment, the slope decreased to 7.0, and the intercept increased to 3.5. After 1 month of rhGH treatment, the a-vO(2) difference (at a VO(2) of 1250 ml/min) significantly (P < 0.05) increased (17.1 +/- 8.9%) from baseline (9.92 +/- 0.51 ml/dl) and remained elevated (10.39 +/- 0.48 ml/dl) after 3 months of treatment. No significant changes were seen with placebo. Therefore, treatment with rhGH leads to an improvement in peripheral muscle oxygen extraction-utilization and the Q-VO(2) relationship during exercise in patients with HIV-associated wasting despite antiretroviral therapy.

The pharmacological treatment of cachexia.

Cachexia is a complex syndrome. The main components of this pathological state are anorexia and metabolic abnormalities such as glucose intolerance, fat depletion, and muscle protein catabolism among others. The aim of the present article is to review the different therapeutic approaches that have been designed to fight and counteract muscle wasting in different pathological states such as cancer, AIDS and chronic heart failure.

Enhanced saquinavir exposure in human immunodeficiency virus type 1-infected patients with diarrhea and/or wasting syndrome.

The protease inhibitor saquinavir was administered to 100 human immunodeficiency virus type 1 (HIV-1)-infected patients as a single 600-mg oral dose (hard gelatin capsules) with a standard breakfast, including 200 ml of grapefruit juice, during an open-label trial to assess whether diarrhea and/or wasting syndrome has consequences on its pharmacokinetics. Three groups of patients were enrolled: group 1, asymptomatic patients (n = 30); group 2, AIDS symptomatic patients without body weight loss or diarrhea (n = 37); and group 3, AIDS symptomatic patients with severe body weight loss and/or diarrhea (n = 33). Clinical and biological data (covariates) were collected. A population approach was performed with three blood samples per patient to estimate the mean population pharmacokinetic parameters (clearance [CL]/oral bioavailability [F], V/F, k(a), and lag time) and the derived ones (k(el), C(max), T(max), and area under the curve [AUC]). The relationships between groups, exposure (i.e., estimated individual post hoc AUCs), and covariates were explored by using multiple linear regressions. A significant increase in median AUCs (165, 349, and 705 ng. h. ml(-1) for groups 1, 2, and 3, respectively [P < 0.0001]) was observed. The enhancement in saquinavir exposure could be due to the destruction of the transporters in enterocytes and/or to the enlargement of their tight junctions, allowing a paracellular crossing of saquinavir as the illness spreads. Because of grapefruit juice intake by every patient, no implication of CYP3A4 could be assessed. These results strongly suggest that, despite its low intrinsic oral bioavailability, saquinavir can be considered as a relevant treatment for HIV-1-infected patients with diarrhea and/or wasting syndrome. This must be evaluated in a long-term period.

Cytokine production in women with antiretroviral treatment-associated breast fat accumulation and limb wasting.

OBJECTIVE: To test the cytokine production of peripheral blood mononuclear cells in a group of HIV-infected women with breast enlargement and lower limb wasting while receiving antiretroviral therapy (ART) including a protease inhibitor. DESIGN: Case-control study including 20 women with fat tissue alterations and 20 matched controls treated with comparable ART. METHODS: Adipose tissue alterations (ATA) were defined by increased breast size (> or = 2 bra sizes) accompanied by lower limb fat wasting. A randomly selected subset of patients underwent analyses including: dual energy X-ray absorptiometry, metabolic and endocrine assays, in vitro cytokine production testing [interferon-gamma, interleukin (IL)-2, IL-4, IL-10, IL-12, tumor necrosis factor-alpha (TNF-alpha)] after appropriate stimulation; T-cell phenotyping, T-helper function after stimulation with either tetanus toxoid, influenza antigen, allogeneic peripheral blood lymphocytes, and phytohemagglutinin. Endocrinological study included the determination of plasma concentrations of prolactin, growth hormone, testosterone, adrenocorticotropic hormone, cortisol and C-peptide. RESULTS: In vitro production of IL-12 was higher (P = 0.0001), and TNF-alpha (P = 0.0093) and IL-10 (P < 0.0001) production were lower in stimulated peripheral blood mononuclear cells of ATA-positive women compared with ATA-negative women. ATA-positive women also showed a better response to tetanus toxoid (P = 0.021) and a lower median fluorescence intensity of CD14/DR (P=0.033). Plasma C-peptide values were higher in ATA-positive women compared with ATA-negative women (P = 0.033), even if in the normal range (< 4 ng/ml) in all but one of the ATA-positive patients. CONCLUSION: HIV-1-infected women who developed breast enlargement and lower limb fat wasting while receiving ART had a favorable immunological profile with efficient IL-12 production and T-helper function, and with TNF-a production in the range of a HIV-negative reference population. These findings suggest that the rescue of some immune functions under ART may be involved in the pathogenesis of this particular adipose tissue disorder.

Immunohistochemical study of apelin, the natural ligand of receptor APJ, in a case of AIDS-related cachexia.

Apelin, a peptide first isolated from bovine stomach extracts, was discovered as an endogenous ligand for the APJ receptor. APJ has been shown to be a co-receptor for human and simian immunodeficiency virus (HIV and SIV). Apelin specifically inhibited the entry of primary T-tropic and dualtropic HIV-1 isolated from different clones expressing antiviral CD4 and APJ. On the basis of these results, we decided to compare the apelin expression level between normal and AIDS-infected tissues by immunohistochemistry. We found that apelin expression was less intense in AIDS-infected tissues compared to normal tissues, in particular in the pancreas, kidney, adrenal glands and lymphoid organs. These results suggest an involvement of this peptide in immunodeficiency and in the immune response to AIDS.

Nutritional supplementation according to energy and protein requirements in malnourished HIV-infected patients.

To evaluate the effects of nutritional supplements on nitrogen and energy balances, body composition and immune parameters, HIV-infected malnourished adult outpatients were prospectively studied. Forty-six patients (4 females and 42 males; 37 +/- 12 y) were supplemented with a polymeric diet (PD) or regular foods (RF) on two consecutive 45-day periods on a crossover design. Weight, skinfold thicknesses, plasma albumin (PA), CD4 and CD8 lymphocyte counts (LC), resting energy expenditure (REE) and urinary nitrogen excretion were measured at baseline, 45 and 90-day. Food intake was weekly recorded by food surveys. Thirty-five patients completed the protocol (18 in Group 1:PD-->RF; 17 in Group 2:RF-->PD). In both groups, weight, fat free mass (FFM), energy balance (EB) and nitrogen balance (NB) increased significantly after PD, whereas LC and PA remained unchanged in both groups. The best results in terms of weight gain were obtained in the PD group and PD plus zidovudine subgroup (n = 8) during the first 45 days (weight gain/FFM gain: 4.8/2.6 kg and 6.8/3.1 kg, respectively). Nutritional supplement with PD, according to the EB and NB goals, was well tolerated and permitted to achieve a significant weight and FFM gain over a 90-day follow-up.

Nutritional supplementation according to energy and protein requirements in malnourished HIV-infected patients

To evaluate the effects of nutritional supplements on nitrogen and energy balances, body composition and immune parameters, HIV-infected malnourished adult outpatients were prospectively studied. Forty-six patients (4 females and 42 males; 37 +/- 12 y) were supplemented with a polymeric diet (PD) or regular foods (RF) on two consecutive 45-day periods on a crossover design. Weight, skinfold thicknesses, plasma albumin (PA), CD4 and CD8 lymphocyte counts (LC), resting energy expenditure (REE) and urinary nitrogen excretion were measured at baseline, 45 and 90-day. Food intake was weekly recorded by food surveys. Thirty-five patients completed the protocol (18 in Group 1:PD-->RF; 17 in Group 2:RF-->PD). In both groups, weight, fat free mass (FFM), energy balance (EB) and nitrogen balance (NB) increased significantly after PD, whereas LC and PA remained unchanged in both groups. The best results in terms of weight gain were obtained in the PD group and PD plus zidovudine subgroup (n = 8) during the first 45 days (weight gain/FFM gain: 4.8/2.6 kg and 6.8/3.1 kg, respectively). Nutritional supplement with PD, according to the EB and NB goals, was well tolerated and permitted to achieve a significant weight and FFM gain over a 90-day follow-up.

The role of exercise in the prevention and treatment of wasting in acquired immune deficiency syndrome.

Involuntary weight loss with lean tissue depletion is a serious and AIDS-defining complication of HIV infection. This article explores definitions of AIDS wasting syndrome (AWS), its etiology, methods of assessing body composition, and pharmacological treatments. Recent research literature on the role of exercise in the prevention and treatment of AWS is reviewed. Included are studies of the safety of exercise, the effects of exercise on the immune system, and the effects of exercise on weight gain and body composition as well as studies of exercise in combination with medications and other interventions. Implications for clinical practice are discussed.

Body composition and nutritional parameters in HIV and AIDS patients.

Undernutrition is a frequent complication of evolutive and chronic HIV (human immunodeficiency virus) infection characterized by bodyweight loss and changes in body composition. The Centers for Disease Control and Prevention define AIDS wasting as involuntary loss of more than 10% of body weight, plus more than 30 days of either diarrhea, or weakness and fever. Wasting syndrome has been considered as a case definition of the AIDS disease since 1987. Wasting syndrome is clearly linked to disease progression and death. Despite the progress under the era of highly active antiretroviral therapy (HAART), wasting is still a problem for people with AIDS. A small part of the weight lost is fat. More important is the loss of "lean body mass", which is mostly muscle. Body composition changes during HIV infection are different from those observed in food deprivation. Under the era of HAART, a HIV-associated adipose redistribution syndrome (HARS) was described that associates subcutaneous lipoatrophy and abdominal obesity linked to various metabolic disorders. Several factors contribute to wasting syndrome. Not only low food intake and poor nutrient absorption, but mainly altered metabolism (increased resting energy expenditure) and specific disturbances in protein turnover, which is also increased. Nutritional evaluation of HIV-infected patients should include the measurement of body composition and analysis of nutritional parameters, including albumin, transthyretin and C-reactive protein. Transthyretin seems to be particularly useful to follow the recovery period of malnutrition.

Flux of amino acids and energy substrates across the leg in weight-stable HIV-infected patients with acute opportunistic infections: indication of a slow protein wasting process.

Increased whole-body proteolysis with muscle protein net degradation has been suggested as one of the causes of weight loss in patients infected with human immunodeficiency virus (HIV). We studied the exchange rates of amino acids and energy substrates across the lower extremity in 16 HIV patients and 16 age-matched controls with similar body cell mass. The patients had either opportunistic infections or chronic diarrhea but no signs of clinical malnutrition. The following findings were obtained in the HIV patients: an augmented peripheral net release of arginine and lysine; an increase in both the negative arterial-venous difference and the efflux of the nitrogen contained in nonmetabolized amino acids; diminished export of 3-methylhistidine; lowered plasma and erythrocyte amino acid concentrations; reduced output of glycerol and furthermore; and neither a net release nor a net uptake of free fatty acids. The findings concerning nitrogen metabolism support the hypothesis that, in the presence of a reduction in protein breakdown, peripheral protein synthesis is severely depressed, making a slow protein wasting process likely to occur. The balances of glycerol and free fatty acids are due not only to the leg tissues but perhaps also in part to increased net retention of these substrates by skeletal muscle.

The metabolic puzzle during the evolution of HIV infection.

Abnormalities in energy, protein, lipid and glucose metabolism have been described in HIV patients since the beginning of the epidemic. With the new antiretroviral agents, nutritional status and survival have improved dramatically. However, since these therapies were introduced, there have been more descriptions of metabolic abnormalities, some of which were similar to and others of which were in conflict with those reported in previous years. This paper reviews the complexity of the metabolic abnormalities in HIV infections before and after the introduction of highly active antiretroviral therapy, and discusses such etiopathogenic mechanisms as secondary infections, antiretroviral drugs and persistent immune activation, which may be involved in these derangements.

Increased oral ganciclovir bioavailability in HIV-infected patients with chronic diarrhoea and wasting syndrome--a population pharmacokinetic study.

AIMS: Despite a lack of data, the antiviral agent ganciclovir is not indicated in AIDS patients with diarrhoea because of its presumed poor oral bioavailability. To assess the effect of diarrhoea on ganciclovir intestinal absorption, we conducted a pharmacokinetic study in 42 HIV-infected patients categorized into three groups: A, HIV stage A and B (n = 15); B, AIDS stage C (n = 13); C, AIDS with chronic diarrhoea and wasting syndrome (n = 14). METHODS: Each patient was evaluated for nutritional (body mass index, albumin, transferrin serum levels), inflammatory (haptoglobin, orosomucoid), immunological (CD4 count, plasma viral load) and intestinal (D-xylose test, faecal fat and nitrogen output, intestinal permeability) status. Ganciclovir (1 g) was administered orally to fasted patients. Six blood samples were collected over 24 h. Serum was analysed for ganciclovir by h.p.l.c. Population pharmacokinetic analysis was performed using a nonlinear mixed effects modelling program, MP2. RESULTS: Mean intestinal permeability (lactulose/mannitol urinary ratio) was increased in group C (0.2) compared with group A (0.05) and B (0.1) patients. Drug concentration-time profiles were best described by a two-compartment model. Apparent oral clearance (CL/F) and central volume of distribution (V1/F) were influenced by clinical status (group). For groups A and B combined, final parameter estimates of CL/F and V1/F were 256 +/- 98 l h(-1) and 1320 +/- 470 l, respectively. Final parameter estimates for group C were 118 +/- 108 l h(-1) and 652 +/- 573 l for CL/F and V1/F, respectively. The 95% confidence intervals on differences between A and B combined and C were statistically significant ([ + 70, + 206] for CL/F, and [+ 314, + 1022] for V1/F). Compared with groups A and B, ganciclovir CL/F was significantly decreased in group C patients. CONCLUSIONS: AIDS patients with diarrhoea and severe disease may benefit from ganciclovir therapy, but a dose adjustment may be required according to their digestive and immunological status.

Osteopenia in eugonadal men with acquired immune deficiency syndrome wasting syndrome.

Multiple endocrine and metabolic consequences of human immunodeficiency virus (HIV) infection exist that may contribute to bone loss in men with the acquired immune deficiency syndrome (AIDS) wasting syndrome. Recent studies suggest that anabolic strategies can increase lean body mass in men with AIDS wasting. Prior studies have not examined the effects of anabolic agents on bone mineral density (BMD) or bone turnover in these men. To determine the effects of testosterone and progressive resistance training on BMD and bone turnover in eugonadal men with AIDS wasting, we randomly assigned 54 eugonadal men with AIDS wasting (weight < 90% IBW or weight loss >10% from preillness baseline) to receive either testosterone enanthate (200 mg/week, im) or placebo and to progressive resistance training (3 times/week) or no training in a 2 x 2 factorial study design for 3 months. The BMD of the lumbar spine, proximal femur, and total body; lean body mass; and fat mass were measured by dual energy x-ray absorptiometry. Total body scans were repeated after 12 weeks of therapy. Baseline bone turnover and BMD were compared with those in 35 age-matched healthy non-HIV-infected control subjects. Compared with controls, lumbar spine BMD (1.021 +/- 0.018 vs. 1.084 +/- 0.025 g/cm(2); P = 0.04) and total hip BMD (0.951 +/- 0.017 vs. 1.070 +/- 0.019 g/cm(2); P < 0.0001) were reduced in men with AIDS wasting. T-scores were lower in men with AIDS wasting at the lumbar spine (-0.62 +/- 0.17 vs. -0.07 +/- 0.23, P = 0.05) and total hip (-0.65 +/- 0.11 vs. +0.20 +/- 0.014, P < 0.0001). Total hip T scores were less than -1.0 in 33% of men with AIDS wasting. Neither the use of protease inhibitors nor the duration of protease inhibitors use correlated with BMD. Serum osteocalcin levels were lower (3.63 +/- 0.29 vs. 4.54 +/- 0.31 nmol/L; P < 0.04) and urinary N-telopeptide excretion was higher (45.4 +/- 4.5 vs. 26.8 +/- 3.0 nmol BCE/mmol creatinine; P = 0.004) in men with AIDS wasting than in controls. Lumbar spine BMD, as assessed on regional total body dual energy x-ray absorptiometry scan, increased over the 12-week treatment period in response to testosterone (+2.4 +/- 1.3 vs. -1.3 +/- 1.0%, testosterone vs. placebo, respectively; P = 0.02), but not in response to training (+0.8 +/- 1.0 vs. +0.4 +/- 1.3%, training vs. no training; P = 0.70). Lumbar spine and total hip BMD are reduced in eugonadal men with AIDS wasting. Biochemical markers of bone turnover suggest that bone formation and bone resorption are uncoupled in these men. Testosterone administration, but not resistance training, over 3 months increases lumbar spine BMD in eugonadal men with AIDS wasting.

Effect of acquired immune deficiency syndrome wasting on the protein metabolic response to acute exercise.

Wasting is a major complication of human immunodeficiency virus (HIV) infection, which remains prevalent even in the era of highly-active antiretroviral therapy. We have previously shown that progressive resistance exercise can increase lean body mass (LBM) significantly in patients with wasting, and that exercise does not increase circulating HIV RNA concentrations. We examined the effect of 1 bout of moderately difficult exercise on whole body protein kinetics in 10 patients with HIV wasting and 12 patients with HIV infection without wasting. At baseline, there were no differences between the groups in whole body leucine flux, oxidation, or nonoxidative leucine disposal (NOLD, a measure of whole body protein synthesis). Six days after exercise, NOLD was significantly higher in the wasted patients compared with the nonwasted ones (82.2 +/- 16.7 v 66.5 +/- 15.2 micromol/kg LBM/h, P <.03). The change in NOLD between baseline and day 6 was significantly different between the 2 groups (+9.0 +/- 9.2 v -3.3 +/- 5.7 micromol/kg LBM/h, P <.02). These data indicate that the ability to respond to exercise with protein synthesis is maintained in HIV wasting.