GH in the patient with emaciation, cachexia and AIDS

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HIV-associated wasting can be defined as the unintentional loss of body weight and lean body mass (LBM) in HIV-infected patients. The Centers for Disease Control and Prevention (CDC) definition of HIV-associated wasting is >10% unintentional weight loss due to chronic diarrhea (2 liters per day for >30 days) or chronic weakness and documented fever for >30 days (intermittent or constant) in the absence of a current condition other than HIV infection that could explain these findings.

HIV wasting syndrome was officially recognized as an AIDS-defining disease for the first time in 1987. Some early studies referred to this disease as AIDS wasting, but these studies were generally conducted before the introduction of highly active antiretroviral therapy (HAART), when wasting was among the most frequently AIDS-defining conditions.

Since the introduction of HAART, treated patients remain HIV-positive long before the onset of AIDS; however, asthenia may occur before progression to AIDS and may be a significant comorbidity in the HIV-positive patient before AIDS.

HIV-associated wasting has been described as a form of cachexia. Cachexia is a state of poor general health and malnutrition characterized by excessive weight loss and accelerated skeletal muscle loss in the context of a chronic inflammatory response; it can occur in numerous chronic and malignant diseases, such as cancer, sepsis, congestive heart failure, inflammatory bowel disease, chronic obstructive pulmonary disease, and HIV. However, there is no commonly accepted definition of cachexia.

The etiology of HIV-associated cachexia is multifactorial and the underlying pathogenesis is not clearly understood, however, evidence suggests that reduced caloric intake and metabolic and endocrine factors play an important role in the development of this condition. Weight loss may occur in association with some HIV-associated opportunistic infections (e.g., microsporidia, Cryptosporidium, Giardia lamblia, cytomegalovirus, Mycobacterium avium) and may be related to gastrointestinal malabsorption.

Multiple coexisting mechanisms of cachexia wasting have been identified. An excessive proinflammatory cytokine response appears to be a common mechanism. Other proposed mechanisms include endocrine abnormalities such as low testosterone levels and GH “resistance,” which are discussed in the following sections.

Elevated levels of the proinflammatory cytokines interleukin (IL)-I, IL-2, IL-6, interferon-7 (IFN-7) and/or tumor necrosis factor (TNF-alpha, also known as cachectin or cachexin) have been observed in acute patients and patients with excessive weight loss, usually with muscle wasting, in the setting of congestive heart failure, chronic renal failure, chronic obstructive pulmonary disease, cancer, and HIV-associated wasting. High levels of cytokines cause alterations in muscle protein metabolism through activation of the ubiquitin and proteasome system. This is a selective protein degradation pathway responsible for the acceleration of proteolysis under catabolic conditions.

The Growth Hormone/Insulin-Like Growth Factor-1 Axis.

HIV wasting can be caused by disturbances in the GH/IGF-1 axis. Maintenance of muscle protein mass involves a dynamic balance between protein synthesis and degradation. Protein metabolism is under the control of numerous hormone and second messenger systems, including glucagon, glucocorticoids, insulin, the polypeptide growth factors IGF-1 and IGF-2, and GH. The effects of GH on muscle appear to be mostly mediated by IGFs, which have anabolic effects such as stimulation of muscle growth and myoblast differentiation. These polypeptides also have protein partitioning effects; for example, IGF-1 suppresses protein degradation and prevents proteolysis.

Preliminary data suggest that HIV infection may cause direct disruption of the GH/IGF-1 axis. An HIV-1 envelope protein (gp120) that is homologous to GH-releasing hormone (GHRH) binds to GHRH receptors in the pituitary gland, potentially suppressing GH release. Evidence from studies in patients with HIV infection indicates that patients with wasting acquired a GH-IGF axis that is altered from the normal physiological state.

Clinical use of rhGH in AIDS wasting syndrome (AWS).

The presence of GH resistance in malnourished AIDS patients, in association with the possible anabolic effects of GH in non-HIV catabolic conditions, has led to the evaluation of the effects of recombinant human GH (rhGH) in these patients. In a small uncontrolled study of short-term (12-week) rhGH in AIDS with AWS, high (5.0 mg sc every other day) but not low (2.5 mg every other day) pharmacological doses of rhGH caused a significant increase in total body weight (3, 2 +/- 2.4 kg) and lean mass (3.8 +/- 1.9 kg) as well as a decrease in fat mass (FM) and a trend toward lower urinary nitrogen excretion, suggestive of an improvement in total body nitrogen balance. However, the increase in body weight returned to baseline within 6 weeks after treatment discontinuation. Mild increases in fasting glucose occurred. GH use causes a state of insulin resistance in non-HIV patients receiving rhGH. Significant increases in fasting glucose and glycosylated hemoglobin occurred in the treated group, as did GH-associated musculoskeletal toxicities.

Because most of the anabolic effects of GH are mediated through IGF-1, and levels tend to be low in AWS, the potential therapeutic benefits of IGF-1, alone or in combination with rhGH, were investigated. In a small study with low or high doses of IGF-1, there was a significant but transient improvement in nitrogen retention, indicating an anabolic response. Total body weight increased only in the high-dose treated group, and FM did not decrease. In this study, a single dose of GH resulted in a slight increase in IGF-1 levels in AWS patients compared with uninfected controls, further supporting the diagnosis of GH resistance. In other studies of AIDS patients with AWS, IGF-1 was used in combination with lower pharmacological doses of rhGH but no anabolic effects occurred.

Conclusions

Improving LBM, particularly muscle protein mass, is an important treatment goal in patients with HIV-associated wasting. In one well-designed clinical trial, rhGH 6 mg/day for 12 weeks was associated with significant improvements in body weight and LBM in patients with >10% body weight loss; however, there were also modest and transient increases in mean blood glucose of -0.6 mmol/l.

There is still much to be learned about rhGH therapy in patients with HIV-associated wasting, such as the optimal duration of treatment, the benefits and risks of continuous or repeated courses of treatment, and the long-term impact of treatment on morbidity and survival. Overall, rhGH promises to be an effective treatment for selected patients, although the individual patient’s metabolic profile and clinical needs must be taken into account when choosing any treatment.

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