Changing Patterns of Cachexia in the HAART

A familiarity with the information on adipose tissue provided in the previous section is necessary to understand the complex nutritional changes related to HIV infection and its treatments. It has long been known that during the progression of HIV infection, as well as of other chronic infections and tumours, patients may undergo progressive weight loss and changes in body composition, particularly in fat and muscle masses, and in metabolic pathways, particularly lipid metabolism [62,

111]. This is known as wasting syndrome [9] or cachexia [2,112].

From 1987 to 1993, wasting syndrome was the AIDS-defining disease in 20% of patients and in up to 70% of patients at the time of death. The incidence of wasting syndrome per 1000 person-years increased from 7.5 in the period 1988-1990 to 14.4 in 1991-1993 and 22.1 in 1994-1995. The incidence decreased to 13.4 in 1996-1999 [113]. Dworkin et al. [19], in a large study, obtained similar results; they found that the incidence of wasting syndrome decreased from 30.2 cases per 1000 person-years in 1992 to 11.9 cases in 1999, with the most significant rate of decline occurring after 1995.

With the introduction of potent antiretroviral combination treatments, including nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTI, NNRTI) and protease inhibitors (PIs), which have prolonged patient survival, the incidence of the previously described changes has been dramatically reduced. Since 1996, when HAART was introduced, the number of patients who died of AIDS and opportunistic infections has decreased by two-thirds, although wasting remains a clinical problem for patients [114,115]. In addition, new disorders involving lipids, glucose metabolism, and body fat have acquired greater clinical importance [116-120]. The changes are characterised by hyperlipidaemia, generalised, central, or peripheral fat redistribution, and hormonal disturbances [116,120-124], and have been named lipodystrophy syndrome, HIV-associated adipose redistribution syndrome (HARS) [125], or metabolic syndrome-X (Tables 5,6,7).

Prior to 1996, only a small percentage (3%) of patients developed hypercholesterolaemia, hyper-triglyceridaemia, and diabetes. The main fat disturbances in cachexia are a decrease in cholesterol levels, an increase of triglycerides, and a global loss of fat together with lean tissue in any body region. These patterns can be clearly distinguished from lipodystrophy (Table 6).

Some of the symptoms and signs of lipodystro-phy were already known before the introduction of PIs, as they occur with d4T-containing regimens without PIs at an incidence of 20% compared to 0% in AZT-containing regimens [126]. After 1996, it was possible to demonstrate a clear time correla-

Table 5. Changes in body shape following protease inhibitor therapy

No change

Mild

Moderate

Severe

Body shape

17%

42%

30%

11%

Loss of subcutaneous fat

32%

31%

27%

10%

Crix belly

35%

30%

22%

13%

Buffalo hump

80%

10%

7%

3%

Table 6. Differences between cachexia and lipodystrophy syndromes

Cachexia

Lipodystrophy

Body weight

0

ft

or

Body fat

-0- All districts

Peripheral 0

Central ft

Lean body mass

Unchanged 0

Total cholesterol

0

ft

VLDL cholesterol

0

ft

LDL cholesterol

0

ft

HDL cholesterol

-

0

Triglycerides

ft

ftft

Diabetes/insulin resistance

No

Yes

Coronary artery disease

No

Yes

tion between changes in fat and glucose metabolism and the introduction of PIs. A significant portion, ranging from 5 to 75%, of HIV patients receiving PIs noted changes in lipid metabolism and body fat distribution [127] after an average time of 10 months with Ritonavir/Saquinavir and more than 1 year with Indinavir. These alterations were seen primarily in 32% of patients treated with Indinavir (Crixivan, MSD; this is the origin of the term 'crix belly') [128]. However, more evident abnormalities, referred to as 'protease paunch'

[129], are caused by other PIs, such as Nelfinavir (Viracept, Agouron; in 39% of patients), and the dual combination of Ritonavir (Norvir, Abbott)

[130] plus Saquinavir (Invirase/Fortovase, Roche; in 66% of patients) [116]. Amprenavir (Agenerase, Glaxo Wellcome/Vertex) seems to have fewer side effects. No data are available for Tipranavir (Texega, Pharmacia Upjohn), DMP-450 (Triangle Pharmaceuticals), and ABT-378 (Abbott).

Abnormal fat accumulation may be visceral (omentum, mesentery, retroperitoneum, pelvic areas), associated with abdominal fullness and bloating (syntomatic fat deposition) [128], or peripheral [116], ranging from benign bilateral symmetric lipomatosis [131] to multiple symmetric lipomatosis and to a dorsal ('buffalo hump') and/or cervical fat pad ('bull neck') [118]. More recently, lipodystrophy syndrome has been better characterised [132-134] with case-definition signs. Fat redistribution (HARS) may have the aspect of either peripheral lipoatrophy/dystrophy, involving the face (loss of buccal, parotid, Bichat's, and preauricular pads, sunken cheeks and eyes, prominent zygomatic arches); buttocks; pronounced thinning of the arms and legs with prominence of subcutaneous veins, muscles, and bones; loss of normal skin texture, folds and trophism; or central lipohypertrophy, with accumulation of fat in the trunk, breast, and/or dorso-cervix, leading to bull

Table 7. Diagnostic criteria for HIV lipodystrophy syndrome

Main criteria

• Loss of peripheral fat tissue

• Increased central fat tissue (abdominal girth)

Minor criteria

• Visible subcutaneous veins

• Loss of temple, nasolabial, and cheek fat pads

• Buffalo hump or bull neck

• Breast hypertrophy

• Enlarged supraclavicular fat pads

• Bilateral symmetric lipomatosis (enlarged axillary fat pads)

• Decreased thighs size

• Hyperlipidaemia (cholesterol, triglycerides)

Adjunctive criteria

• Peripheral insulin resistance

• Hyperinsulinism

• Hyperuricaemia

• Low serum testosterone

• Increased C-peptide

• Increased free fatty acids

• Coronary artery disease, ischaemic heart disease

Hypertension neck, buffalo hump, and enlargement of abdominal girth and the breasts in women (Fig. 10,11).

The changes in body shape negatively affect the patient's self perception, with negative consequences on compliance. Female patients especially are psychologically distressed by the changes in their body shape. For this reason, many patients stop PI treatment, with the subsequent risk of progression of HIV infection. Lipodystrophy syndrome also affects HIV-infected children, with a prevalence of 26% for any fat redistribution, 8.81% for central lipohypertrophy, 7.55% for peripheral lipoatrophy, and 9.64% for a combined type [135].

Simple measurement of skin folds, hips, and the waist [136, 137] is important to monitor and compare self-reporting symptoms and real changes in body fat redistribution. A finer assessment may be done using bioelectrical impedance assay [138, 139], dual-energy X-ray absorptiometry [119, 140, 141], magnetic resonance imaging

[142, 143], computed tomography [144, 145], or ultrasonography [146].

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